Expanding access to monoclonal antibody-based products

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wellcome.ac.uk iavi.org Executive summary

Monoclonal antibodies are one of the most powerful Identifying pathways to provide affordable, timely tools in modern medicine. More than 100 of them and sustainable access to monoclonal antibody- have been licensed over the past 30 years and they based products across the globe is therefore a are transforming the way doctors treat, prevent and global health priority. even cure serious non-communicable diseases, including many cancers and autoimmune disorders. There is not a simple solution to this problem. These monoclonal antibody products are significantly Monoclonal antibodies are more complex and more effective than previously available therapies expensive to develop and produce than small and are often better tolerated and easier to deliver. molecule generic drugs. And the business and There’s also a rapidly growing pipeline of monoclonal partnership models that have vastly expanded antibodies to treat and prevent many existing and global access to some HIV drugs are not necessarily emerging infectious and neglected diseases. applicable or sufficient. Ensuring monoclonal antibodies are available and affordable globally Millions of people around the world stand to will require new ways of thinking, new types of benefit both from existing monoclonal antibody- collaboration and new ways of doing business. based products and those in development. Rates of non-communicable diseases are on the rise in This report identifies a series of parallel actions many developing countries. In addition, there are that are required to expand access to monoclonal numerous existing and emerging infectious disease antibodies. The process starts with advocacy and

99% of deaths from For global access to monoclonal respiratory syncytial virus occur in low- and middle- 99% of the sales of antibodies to be a reality, these income countries. Synagis, an antibody- innovative products have to be based preventive, are in the US and Europe. both available and affordable.

threats, including COVID-19, Ebola and HIV, for awareness, but it also requires that regulatory and which monoclonal antibodies are poised to play policy issues are addressed, and that technological an important role in treatment and prevention. As advances are applied throughout the process of the COVID-19 pandemic has shown, no country is identifying, optimising, producing and delivering immune to the threat posed by emerging infectious more potent, lower-cost monoclonal antibody diseases. If monoclonal antibodies prove to be products. New business models that promote the effective for COVID-19, ensuring prompt, equitable availability and affordability of these products are and affordable global access to these products, as also necessary. Together, these actions will make it well as others, will be imperative. possible to address the growing inequity to these products, saving or improving millions of lives in the But as this report details, global access to process. monoclonal antibody products is now severely limited in many countries. Today, the market for Progress can’t come soon enough. The goal of this monoclonal antibodies is overwhelmingly in high- report is to catalyse discussion, collaboration and income countries. Few, if any, monoclonal antibodies action. Pharmaceutical companies, global health are registered in low-income countries, and those agencies, public sector entities, philanthropic that are registered in many middle-income countries organisations and ministries of health must join are often unavailable in their public health systems, forces to make global access to transformative making them prohibitively expensive. This gap monoclonal antibody products a priority, and a in access will only widen because monoclonal reality. antibodies are an increasingly large proportion of pharmaceutical company pipelines. The time to act is now.

4 | Expanding access to monoclonal antibody-based products Reshaping the monoclonal antibody world

Today’s global market for monoclonal antibodies is highly unbalanced.

US, Canada and Europe Note: Percentages are rest of world approximate

Ensuring equitable access requires four parallel yet vital commitments.

Increase Expand Apply Create awareness availability innovations new models

Spread the word Support broader Invest in and Establish that monoclonal registration deploy new business models antibodies save of antibody technologies to that enable lives products across lower development different market the globe costs approaches and promote access Table of contents

07 Methodology

08 Monoclonal antibodies are transforming human health 12 Global need, but not global access 14 Case studies

18 What will it take to make monoclonal antibodies globally accessible?

20 Monoclonal antibodies are only accessible if they are available 22 Harmonising regulatory pathways 24 Expand and utilise policy pathways for mAb access 26 Raise awareness of the health benefits of mAbs 26 Strengthen healthcare systems and the ability to diagnose disease

28 Making monoclonal antibodies more affordable 30 Factors influencing global mAb prices 32 Validate and apply novel technologies to lower costs 39 Innovative approaches to intellectual property to expand access 39 Implement new business models that prioritise access 42 Establish procurement and delivery models to enable greater access

44 A roadmap for expanding global access to monoclonal antibodies

49 References

Appendix (presented separately) 2 Stakeholders list 5 Monoclonal antibody products approved or under review in the European Union and United States 11 Trastuzumab biosimilars 13 Pipeline of monoclonal antibodies for emerging, neglected and endemic infectious diseases and pathogens 34 Isolation of antibodies 38 Biosimilar guidelines in BRICS-TM

6 | Expanding access to monoclonal antibody-based products Methodology

Scope The goal of this report is to assess the factors impeding access to mAbs in low- and middle-income countries, particularly within public health systems, and to formulate a series of recommendations for expanding global access to affordable antibody therapies. The classification of low-, middle- and high-income countries is based on World Bank classifications.

The report highlights opportunities for expanding access to monoclonal antibodies for cancers and autoimmune diseases, as well as those for neglected and viral/bacterial infectious diseases that are anticipated to represent a significant percentage of the future antibody market. These include antibodies against SARS-CoV-2, HIV, respiratory syncytial virus (RSV), rabies, Ebola, filoviruses, viral enteric pathogens and gram negative bacterial enteric pathogens, including E.coli, Klebsiella p., Shigella and Salmonella, which are on the World Health Organization’s (WHO) and the US Centers for Disease Control and Prevention’s lists of critical drug-resistant pathogens, as well as gram-positive bacterial enteric pathogens such as C. difficile.

Approach, data collection and analyses were monoclonal antibodies to illustrate the impact they based on two methods. A robust assessment was have had on non-communicable, communicable conducted of peer-reviewed biomedical literature, and neglected diseases, and to evaluate the news sources, organisational websites, drug availability of the products and their impact in labels, recognised global and national datasets high-, middle- and low-income countries for which (including those available from the Institute for data are available. Case studies were selected Health Metrics and Evaluation), the WHO, clinical because they cover a broad range of mAbs trial registries, national regulatory agencies, for non-communicable diseases (cancers and national patent offices, drug pricing databases and autoimmune diseases), communicable diseases market reports to capture the current state of the (RSV and C. diff infections) and neglected diseases innovative and biosimilar mAb markets. Reports on (rabies). The case studies cover antibodies that antibody pricing models, with a focus on access to were approved more than 15 years ago (e.g. antibodies in public health systems in LMICs were Herceptin®, the first targeted antibody for breast analysed, and Charles River Associates (CRA) was cancer; Humira® and Enbrel®, which are the gold commissioned to extract more detailed information standard treatments for rheumatoid arthritis; and on pricing pressures and models, with a focus on Synagis®, the first licensed preventive antibody understanding global access challenges. for an infectious disease); as well as other more recent approvals (e.g. Keytruda®, Rabishield®, Additionally, a series of more than 100 interviews were Twinrab®, and Zinplava®). A landscape analyses conducted with global-health focused organisations, of emerging, neglected and endemic infectious ministries of health, academic institutions, regulatory disease mAbs and more detailed examination of authorities, antibody-focused biosimilar/biotechnology some pipeline monoclonal antibodies for infectious companies and multinational pharmaceutical diseases, including COVID-19, HIV, Ebola, Nipah/ companies with large antibody pipelines. Focused Hendra and influenza, are included in supplemental stakeholder meetings were convened in India, where sections of this report. Supplemental sections local participants and influencers were invited to of this document cover the following topics: discuss the challenges and opportunities for global the emerging role of monoclonal antibodies in access to antibodies. Smaller group discussions and epidemic/pandemic preparedness and response; individual stakeholder consultations were convened in monoclonal antibodies: a new era in the treatment sub-Saharan Africa (SSA) and in several high-income and prevention of disease; the development of countries. The list of organisations consulted in this HIV-specific broadly neutralising antibodies; process is on page 2 of the Appendix to this report. combination monoclonal antibodies and alternate formats; and India’s biopharmaceutical business: Several case studies were then selected of licensed an evolving success story.

7 | Expanding access to monoclonal antibody-based products Monoclonal antibodies are transforming human health

Key findings: Monoclonal antibodies (mAbs) are one of the most powerful tools in modern medicine.

An analysis of select licensed mAbs for both non-communicable and infectious diseases indicates that availability (including registration, inclusion on national medicine lists and reimbursement through public health systems) and affordability are two of the biggest barriers impeding global access.

Most licensed mAbs are for non-communicable diseases, including cancer and autoimmune diseases.

Only seven of more than 100 currently licensed mAbs are for infectious/neglected diseases; however, mAbs are poised to play a major role in treating and preventing infectious/neglected diseases that disproportionately impact developing countries, as well as emerging pathogens with the potential to spread globally.

mAbs are a large and growing segment of the pharmaceutical market and are the largest class of biologic products in development.

When and where lower-priced biosimilar mAbs are available, they can increase access, but not sufficiently.

Monoclonal antibodies are one of the most powerful tools in modern medicine. These proteins act What are monoclonal antibodies? specifically against their targets — anything from viruses and bacteria to cancerous cells — and can Antibodies are proteins safely and effectively prevent or treat a growing generated by the immune number of diseases (Figure 1, next page), some of system. They are one of the which were previously difficult, if not impossible, to primary ways the body defends treat. Millions of people have benefited from mAb- itself against disease. based therapies in the 30 years since the first one was licensed. Polyclonal antibodies are mixtures of naturally occurring antibodies For more, see the supplement to this report: expressed from different immune Monoclonal antibodies: a new era in the cells. They are extracted from human treatment and prevention of disease or animal blood and are used in serum or convalescent plasma-based therapies to treat The majority of licensed mAbs are used to treat diseases including COVID-19, rabies and snakebite. non-communicable diseases, including cancers and autoimmune diseases. Today’s successful Monoclonal antibodies are single antibodies cancer immunotherapies — including more than 40 expressed from identical immune cells that can licensed mAbs that directly or indirectly stimulate be manufactured at commercial scale using cell the immune system to attack and kill tumor cells systems. These human-like proteins are a powerful — are revolutionising cancer treatment and have tool in treating and preventing disease. significantly improved overall and long-term survival

8 | Expanding access to monoclonal antibody-based products Figure 1: Number of monoclonal antibodies approved or under review in the European Union or the United States

Cancers 43

Autoimmune diseases 28

Infectious diseases* 9

Blood disorders 7

Ophthalmic diseases 5

Neurological diseases 4

Cardiovascular diseases 3 Bone diseases 3

Transplant rejection 2

Lymphatic diseases 2 Urologic diseases 1 0 10 20 30 40 50

*Infectious diseases mAbs include five licensed in US/EU, two licensed in India, and two novel mAbs under review. Source: Reichert (2020), The Antibody Society (www.antibodysociety.org)

compared to conventional approaches such as chemotherapy (Figure 2). Figure 2: Impact of pembrolizumab in non-small cell lung cancer patients Only seven mAbs are licensed for infectious Overall 100% 1 diseases. But that is poised to change. There survival is a growing pipeline of mAbs in development 90 for infectious and neglected diseases as well as 80 antimicrobial-resistant bacteria, all of which are Pembrolizumab significant and escalating threats to global public 70 health (Figure 3, next page; see Appendix, page 13). 60 Chemotherapy Antibodies are now being explored for treatment 50 and prevention of a wide range of viral diseases 40 including Zika, dengue, Ebola, influenza, HIV and the newly identified coronavirus, SARS-CoV-2, 30 which was first identified in China in late 2019 and Hazard ratio for death: was classified as a pandemic by the WHO in March 20 0.60 (95% CI, 0.41–0.89) P=0.005 2020. Recent technological advancements have provided an opportunity to quickly isolate, develop 10 and produce therapeutic or preventative mAbs as a complementary approach to vaccine development 0 3 6 9 12 15 18 21 as part of preparing for or responding to current Month and future epidemics/pandemics. Source: Reck (2016) N Engl J Med

For more, see the supplement to this report: The emerging role of monoclonal antibodies in epidemic/pandemic preparedness and response Republic of the Congo, where several recent Ebola Many efforts are underway to evaluate the potential outbreaks have occurred. Clinical data suggest of using mAbs to treat or prevent COVID-19, and that therapeutic Ebola mAbs2,3, in combination two experimental mAb products against Ebola with the recent approval of the first Ebola vaccine are already being administered as part of an (ERVEBO®), could prove a powerful duo in treating emergency access programme in the Democratic and preventing this viral infection4.

9 | Expanding access to monoclonal antibody-based products Figure 3: Number of monoclonal antibodies in development and licensed for infectious diseases and pathogens

Emerging and neglected diseases

SARS-CoV-2 0 0

Priority antimicrobial resistance pathogens 0 0

Influenza 0 0 0

Human immunodeficiency virus

Enteric diseases 0 Key to chart 0 Bars reflect the number of monoclonal antibodies at each stage of development:

Respiratory Preclinical

syncytial virus 0 Phase I/II Phase IIb/III Under review Cytomegalovirus Licensed 0 0

E. coli 0 0 0

0 Malaria 0 0 0

Mycobacterium 0 tuberculosis 0 0

0 10 20 30 40 50 60 70 Emerging and neglected diseases are chikungunya, Crimean Congo hemorrhagic fever, dengue, Ebola, Sudan, Bundibugyo, Marburg, Junin Virus, Lassa, MERS, SARS, Nipah, Hendra, Rift Valley fever, rabies, severe fever with thrombocytopenia syndrome, Zika virus disease Priority antimicrobial resistance pathogens are Acinetobacter baumannii, Campylobacter, Enterobacter, Enterococcus faecium, enterovirus, Helicobacter pylori, Klebsiella pneumoniae, Morganella spp, Proteus, Providencia spp, Pseudomonas Aeruginosa, Salmonella Typhi, Shigella, Staphylococcus aureus, Streptococcus pneumoniae Enteric diseases are adenovirus, astrovirus, cholera, Clostridium difficile, hepatitis A, B and E, norovirus, rotavirus, typhoid E. coli and Klebsiella pneumoniae are both enteric and antimicrobial resistance pathogens and are listed separately For HIV there are multiple mAbs that are being tested alone or in combination. Repurposed mabs for SARS-CoV-2 symptomatic treatment not shown. Two anthrax mAbs not shown Preclinical numbers represent the number of institutions/programs. The clinical numbers represent numbers of antibodies, unless otherwise stated. Source: IAVI pipeline analysis

10 | Expanding access to monoclonal antibody-based products Figure 4: Top 10 drugs by global sales, in 2019

In billions of US dollars

® mAbs for Humira $19.2 autoimmune ® diseases Stelara $6.4

mAbs for Keytruda® $11.1 cancers Opdivo® $7.2

Avastin® $7.1 Rituxan® $6.5 Herceptin® $6.1

® Small Revlimid $9.7 molecule Eliquis® $7.9

Vaccine Prevnar® $5.8

0 5 10 15 $20

Source: Urquhart (2020) Nat Rev Drug Discov.

The use of mAbs to both prevent and treat HIV infection is another flourishing area of research. Monoclonal Several antibodies that can act against the diverse strains of the virus (so-called broadly neutralising antibodies are antibodies or bnAbs) are in development and may offer new hope in battling HIV, which still newly the single-largest infects about two million people each year.

For more, see the supplement to this report: class of biologic The development of HIV-specific broadly neutralising antibodies molecules

Data from the first proof-of-concept trial testing undergoing clinical whether a single bnAb can prevent HIV infection is expected in 2020. Meanwhile, researchers are investigation. applying technological advances to optimise HIV-specific bnAbs and increase their potency, thereby lowering the dose necessary to provide protection in animal models5. Many optimised HIV bnAbs delivered subcutaneously in combination or in a single, multispecific antibody format are in development. These more potent antibodies have the potential to be more affordable globally 6. page 5) have been licensed or submitted for regulatory review, with approval rates rapidly Transforming lives, increasing. More than 50 mAbs were licensed transforming markets in the last six years1. In 2019, seven of the ten best-selling novel drugs were mAbs for cancer and Given their numerous applications, the development autoimmune diseases7 (Figure 4). of mAb products is one of the fastest growing segments of biomedical research. Since 1985, over Monoclonal antibodies are also the single- 100 mAbs (Figure 3, previous page; see Appendix, largest class of biologic molecules undergoing

11 | Expanding access to monoclonal antibody-based products Global need, but not global access

Given the growing number of non-communicable and infectious diseases for which mAbs are or might be an effective treatment or preventive, there is clearly a global need for these products. Yet mAb sales are predominantly in the US, Canada and Europe (see map). Low- and middle-income countries (LMICs), which account for 85 per cent of the global population, lag far behind in mAb sales and access to these innovative products17,20,55.

In low-income countries, few if any mAbs are even registered (see figure below). India represents one of the best-case scenarios with respect to the availability of mAbs in middle-income countries, largely because of its extensive biosimilar manufacturing capacity and the resulting competition among biosimilar products, yet even there, fewer than 22 per cent of the products in the US market are available, and no mAbs for cancer therapy are currently available in the Indian public health system19,56. As the percentage of mAbs in development pipelines are increasing8, more and more mAbs will enter the market, and the disparity in access between high-income countries and the rest of the globe will likely only worsen.

Number of registered monoclonal antibodies in selected countries (includes biosimilars) 0 20 40 60 80 100 120

EU 120

US 112

Brazil 77

India 36 US, Nigeria 10 Canada, Europe Zimbabwe 7

Mideast Asia- Sources: IAVI registration analysis (chart) Estimated global Pacific Coherent Market Report, 2019 (map) market for monoclonal antibodies, 2018 Africa 4% The majority of deaths from non-communicable Latin America diseases occur in low- and middle-income countries.

clinical investigation. The percentage of biologics in improve response rates10. There is also a growing development has doubled in the past two decades interest in different types of antibody formats (increasing from 20 per cent of pharmaceutical including antibody-drug conjugates (ADCs), pipelines in 1995 to more than 40 per cent in 2018)8. antibody-protein fusions, antibody fragments, More than 570 mAbs are now in clinical testing—60 single-chain antibodies and multispecific formats. per cent of which are for oncology—and hundreds Multispecific antibodies offer an alternative to more are in preclinical development for a range of combinations of multiple mAbs, each binding a diseases9. distinct epitope. All of these alternate antibody formats can expand the therapeutic potential of Increasingly, combination mAbs are also being mAbs and allow for various modes of delivery11–13. developed to address the emergence of drug- resistant strains or escape mechanisms for many diseases, including HIV, antimicrobial resistant For more, see the supplement to this report: infections and cancer. Combining mAb products Combination monoclonal antibodies can increase the breadth of functional activity and and alternate formats

12 | Expanding access to monoclonal antibody-based products There is also a growing market of biosimilars, which 36 biosimilar mAb products already on the market are lower-priced versions of licensed mAbs that have and another 37 in the pipeline19,20. In 2017, Biocon, no clinically meaningful differences to the originator a leading Indian biosimilar company, successfully product in terms of mechanism of action, safety, registered Ogivri® (a biosimilar of the breast cancer purity and potency. While somewhat akin to generic mAb trastuzumab) in the US in partnership with drugs, biosimilars are not identical copies of the Mylan, making it the first Indian company to have originator mAb and, as a result, their development a US Food and Drug Administration (USFDA)- is significantly more complex and costlier. It is on approved biosimilar21. average 50–100 times more expensive to develop and manufacture a biosimilar than a small molecule India is also a leader in developing small molecule generic. It also takes eight to ten years to develop generic drugs. Its strength and leadership in biosimilars, compared to only three to five years for developing and manufacturing both biosimilars and generics14. generics stems partly from the country’s historical intellectual property laws that did not uphold In many countries, biosimilars enter the market product patents. In 2005 India amended its patent once the 20-year period of patent protection on the laws to comply with TRIPS (Trade-Related Aspects originator mAb expires. However, in some cases, of Intellectual Property Rights) obligations, but in inventors can obtain secondary patents based the 35-year period prior to that, the country built on new uses or formulations of an existing mAb extensive drug manufacturing capacity22. The Indian product. These secondary patents are the primary government also supports the development of both reason the introduction of biosimilars is delayed in innovative and biosimilar mAbs. some markets, particularly the US, where companies are more likely to file secondary patents to protect For more, see the supplement to this report: market share. Europe, India, Argentina, Brazil, Japan India’s biopharmaceutical business: and the Philippines typically allow biosimilars to an evolving success story enter the market earlier than other countries15. Low-cost/high-volume pharmaceutical and vaccine With patent expirations for some blockbuster mAbs manufacturers in India, including the Serum Institute expected in the next few years, many companies of India Private Ltd., Gennova Biopharmaceuticals are now developing both innovative and biosimilar and Sun Pharma, are now investing in both biosimilar mAbs16. Biosimilar development is thriving in India, and novel mAb development, and are increasingly the European Union (EU), the US, South Korea and focused on developing products that address China, with India a clear leader. domestic priorities23,24.

The Indian biosimilar market was evaluated at Globally innovative and biosimilar mAb products US$2.7 billion in 2018 and is anticipated to reach are a large and growing market. In 2018 the global approximately $6.19 billion by 202417. More than mAb market had an estimated value of $111.7 billion. 100 Indian biopharmaceutical companies are Its value is expected to increase to $319 billion manufacturing and marketing biosimilars18, with by 2026 17.

Despite a global disease burden, access to monoclonal antibody products is predominantly restricted to high-income countries. Conclusion This imbalance is preventing the vast majority of the world’s population from benefiting from monoclonal antibody treatments and preventives and it is only likely to grow as more monoclonal antibodies enter the market.

13 | Expanding access to monoclonal antibody-based products Case studies: Factors affecting broader access

An analysis of select licensed mAbs is presented here to illustrate the major factors impeding more equitable global access to these products. The mAbs evaluated are for a range of infectious (RSV, C. diff and rabies) and non-communicable diseases (cancers and autoimmune diseases) and include both older and more recently licensed products. The priority for this analysis was evaluating access to mAbs outside of high-income countries (HICs), but in many cases, access in low-income countries was difficult to assess due to limited data. Data on non-communicable disease (NCD) mAbs are presented first as they represent the vast majority of all licensed products. While there is a rapidly growing pipeline of mAbs for infectious/neglected diseases, antimicrobial-resistant infections and emerging infections, only seven of these products are licensed and therefore access data is more limited.

Monoclonal antibodies for non-communicable diseases

Monoclonal antibody therapies are transforming the treatment of cancers and autoimmune diseases. However, access to these products, even those licensed decades ago, is still predominantly in HICs. The mAb products analysed are largely unavailable in many LMICs, despite a large and growing disease burden in these countries. The majority of deaths from leading NCD-related causes—including 70 per cent of cancer deaths—occur in LMICs25,27, where they are now the leading cause of mortality.

In all cases presented here, lack of availability—either because the product is not registered or it is not available in public health systems—and high prices are the major factor impeding access. Lower-priced biosimilars are helping expand access in some MICs, particularly India, but prices are still too high to make them widely accessible.

® HERCEPTIN MONTHLY COST (trastuzumab) Price of four weekly doses of 2 mg/kg for a 75 kg patient. In US dollars. $12,000 Company $7,480 10,000 Genentech/Roche 8,000 $6,340 Kanjinti® First approved $4,356 6,000 $2,120 1988, United States $2,112 $1,260 4,000 $1,908 Herclon Kanjinti Primary indication 2,000 $580 $476 HER2+ breast cancer Herclon® CanMab® 0 United China United South India Impact States (2018 price) Kingdom Africa HER2+ breast cancer has (2018 price) gone from worst to first ACCESS FACTORS because of the success of Herceptin in combination • Annual costs range from $5,712 to • A 2013 survey showed it is available at with chemotherapy $89,760, based on pricing data half of the healthcare facilities in listed in different countries28–32,98 14 sub-Saharan African countries, but fewer than 5% of patients could afford it35 • Herceptin® global sales were $6.1 billion in 20197 • Several biosimilars available, including four approved by the USFDA, five by the • 12% of women in the United States European Medicines Agency (EMA) and and 50% of women in Europe and China at least three approved products for use did not receive trastuzumab or any other Notes: Kajinti® and CanMab® in low- and middle-income countries (see

are biosimilars. Herclon® is a HER2+-targeted agent, with price being Appendix, page 11), but data is limited “second brand” of Herceptin®— the most significant barrier to access33 a lower-priced version made on how this has expanded access by the same company but • A subset of oncologists in high- and marketed with a different name and sometimes with unique upper-middle income countries reported packaging. Prices are as of insurance coverage, drug availability and February 2020 unless noted. expense were main barriers to access34

14 | Expanding access to monoclonal antibody-based products Monoclonal antibodies for non-communicable diseases (continued)

® KEYTRUDA MONTHLY COST (pembrolizumab) Price of 200 mg every three weeks. In US dollars. $12,000 $11,668 Company 10,000 Merck 8,000 $6,980 First approved 6,000 $5,200 2014, United States 4,000 $2,522 Primary indication 2,000 Melanoma 0 United China United India Impact States Kingdom Keytruda® has significantly improved survival rates of ACCESS FACTORS melanoma, lung cancer and eight other difficult- • Annual treatment costs range from • Access in public health systems and to-treat cancers $42,874 to $198,35630–32 low- and middle-income countries is severely limited because of high ® • Keytruda global sales were treatment costs $11.1 billion in 20197 • Added to the WHO essential medicines • Most patients in Brazil are unable to list in 2019, but unclear how this will access it through the public health affect access in low- and middle-income 36 system because of its high price countries38 • An oncologist in India reports “only one • No biosimilars available in 1,000 of my patients can actually afford to use this drug”37

® HUMIRA MONTHLY COST (adalimumab) Price of two doses of 40 mg every other week. In US dollars.30-32 $12,000 Company 10,000 AbbVie 8,000 First approved $6,208 6,000 2002, United States $918 4,000 Primary indication $842 $280 ® 2,000 Hyrimoz ® Rheumatoid arthritis $366 Exemptia 0 United China United India Impact States Kingdom In patients who do not respond to conventional ACCESS FACTORS treatments, Humira can suppress disease activity, • Humira® is the best-selling prescription • Introduction of biosimilars in Europe slow or stop progression drug in the world, with sales of in 2018 led to an 80% price reduction of joint/radiologic damage approximately $19.2 billion in 20197 of Humira® in some European markets39 and prevent further loss of • Unavailable in India until the launch of • As of 2019 there are four USFDA- quality of life biosimilars in 2014, despite 12 million approved biosimilars in the US, people in the country having conditions with another three in development, that could benefit from its use40 but none of them is expected to launch before 2023 when patent 39 • First available in China in 2010 protection expires20 • Still unregistered in some sub-Saharan

Note: Hyrimoz® and Exemptia® African countries including Zimbabwe are biosimilars. and Nigeria

15 | Expanding access to monoclonal antibody-based products Monoclonal antibodies for non-communicable diseases (continued)

® ENBREL MONTHLY COST (etanercept) Price of four weekly 50 mg doses. In US dollars.30–32 $12,000 Company 10,000 Amgen/Pfizer 8,000 $6,668 First approved 6,000 1998, United States $928 4,000 $472 Primary indication $852 $392 2,000 Benepali® Rheumatoid arthritis Intacept® 0 United United India Impact States Kingdom In patients who do not respond to conventional ACCESS FACTORS treatments, Enbrel can suppress disease activity, • Enbrel® global sales were $5.2 billion • Samsung Bioepis’s biosimilar is approved slow or stop progression in 201941 in 38 countries but there is limited data of joint/radiologic damage on access42 • A few biosimilars became available and prevent further loss of after expiration of the Enbrel® European • Biosimilars are unavailable in the US 39 quality of life patent in 2015 despite USFDA approval because

Note: Benepali® and Intacept® of secondary patents extending until are biosimilars. 2028 or 202943

Monoclonal antibodies for infectious diseases

Availability of these select mAbs is severely limited, even in countries where the need is greatest. Where available, high prices are the biggest barrier to access, with the exception of Rabishield® and Twinrab®. Another barrier to access for some of these mAb products is that they are not optimised for use by all populations in LMICs. This analysis highlights the importance of designing and delivering infectious/neglected disease mAbs that are aligned with patient, healthcare provider and policy maker preferences. This may include antibodies that are effective against a broad range of strains (e.g., rabies) or provide longer-lasting protection (e.g., RSV).

® ZINPLAVA MONTHLY COST ACCESS FACTORS (bezlotoxumab) Price of single-dose treatment. In US dollars.31,44,45 • Merck is conducting clinical Company $5,000 $4,560 trials in several middle-income Merck countries, including Colombia, 4,000 Czechia, Malaysia and South $3,221 Africa46 First approved 3,000 2016, United States • No evidence of access in 2,000 low- and middle-income Primary indication countries Prevention of Clostridium 1,000 difficile infection • No biosimilars available 0 United United Impact States Kingdom The only licensed mAb to (2017 price) prevent (in combination with antibiotics) an enteric disease. C. diff is the leading cause of healthcare -associated infections47

16 | Expanding access to monoclonal antibody-based products Monoclonal antibodies for infectious and neglected diseases (continued)

® SYNAGIS MONTHLY COST (palivizumab) Price of a 15 mg/kg dose for a 3.5 kg patient. In US dollars.

$5,000 Company MedImmune 4,000 $3,564 (AstraZeneca) 3,000 First approved 2,000 $1,500 1998, United States $734 $965 1,000 Primary indication Prevention of respiratory 0 syncytial virus infection United United Malaysia Costa Rica States Kingdom (2015 price) (2015 price) Impact The only licensed mAb ACCESS FACTORS to prevent respiratory • Price ranges from about $3,600 to • Access is limited by the cost and lack of syncytial virus infections, $17,820 per season (five doses), inclusion on national medicines lists the second-leading cause depending on the country30,31,48,49 of death in children during • Synagis® global sales were $665 million the first year of life • Marketed in over 80 countries but, in 2018, with more than 99% of the sales 21 years after its initial approval, access from US and EU markets despite 99% Note: Prices are as of February in low- and middle-income countries of respiratory syncytial virus deaths in 2020 unless noted. remains limited50 low- and middle-income countries52,229 • Not currently licensed in China or Nigeria, • Efforts are underway to develop two countries with high25 RSV incidence51 a biosimilar that is 20-fold less expensive53 • No biosimilars available

RABISHIELD® TWINRAB®

Company Impact Company Impact Serum Institute of India Uptake has been modest so far Zydus Cadila A combination of because of competition from two mAbs expected First approved treatment with human rabies First approved to protect against 2017, India immune globulins/equine rabies 2019, India resistant rabies immune globulins and a lack of strains that are not Primary indication assurance of a large market* Primary indication covered by the single Rabies Rabies antibody product (Rabishield®)54

MONTHLY COST MONTHLY COST A single dose treatment in India is priced at about Anticipated price of $20 to $40 vial* $20 a vial for an ~0.2 mg/kg dose.32

ACCESS FACTORS ACCESS FACTORS • Available in India as well as some other countries, • Available only in India under orphan review by USFDA • Efficacy, strain coverage, price • Doesn’t satisfy WHO’s recommendation that a mix of and market size will ultimately at least two antibodies with non-overlapping epitopes determine uptake is needed to protect against escape mutants228 • No biosimilars available • One of the least expensive marketed mAbs • No biosimilars available

*Consultation with Serum Institute of India, October 2019 *Consultation with WHO, 29 June 2020

17 | Expanding access to monoclonal antibody-based products What will it take to make monoclonal antibodies globally accessible?

To expand global access to mAbs, they must be available and affordable.

The following sections describe the barriers impeding broader access to mAbs as well as solutions to overcoming these barriers, which, if taken, could dramatically increase access and save or improve millions of lives in the process.

18 | Expanding access to monoclonal antibody-based products availability

Harmonize and expand existing Raise awareness of the clinical, Strengthen healthcare systems policy and regulatory pathways public health and economic and the ability to diagnose and explore new ways to value of mAbs through disease in low- and middlie- encourage wider registration concerted advocacy efforts income countries to support of mAbs in low- and middlie- a more accurate assessment income countries of the market need for mAb products and to enable their implementation + affordability

Validate and apply novel Implement alternate business Identify procurement and technologies to drive down models that prioritize access delivery models for mAbs mAb development and similar to those used to manufacturing costs increase affordability of vaccines = access

19 | Expanding access to monoclonal antibody-based products Monoclonal antibodies are only accessible if they are available

Key findings: Many mAbs are not available in low- and middle-income countries because of long delays in regulatory filing, approval and launch of these products, which creates a huge gap in access.

Capacity constraints, unclear or undefined regulatory policies and a lack of market incentive are all barriers to companies more broadly registering mAb products.

Those mAbs that are registered are often still unavailable or have extremely limited availability in the public health systems in low- and middle-income countries.

Efforts are underway to harmonise regulatory approval pathways across low-income settings.

Of the harmonisation efforts underway, only the WHO prequalification pilot program has been applied to biosimilar mAbs, and only one mAb has been prequalified so far.

Incorporating mAbs into WHO policy guidance is one way to support adoption of these products more globally.

Several mAbs were added recently to the WHO’s Model List of Essential Medicines, but it is too soon to tell how this will expand access.

Advocacy efforts related to mAb access are limited or non-existent.

Efforts to demonstrate a public health value proposition—including economic modelling of the impact of mAbs—can help bolster the case for making mAbs more widely available in low- and middle-income countries.

Health systems strengthening and improving the capabilities to diagnose and treat disease in developing countries can help define the market size and support demand forecasting for mAb products to catalyse investments and access in these countries.

Engaging communities, healthcare providers and policy makers will help ensure that future products are acceptable and feasible to implement in diverse settings.

One major barrier to global mAb access is 43 per cent of priority LMICs, including 13 of 46 that many of these innovative products are not sub-Saharan African (SSA) countries. even available in many low- and middle-income countries. There are several factors that contribute to these registration delays, or lack of filings altogether. This is partly because there are long delays for One of the biggest factors is that pharmaceutical filing, approval and launch of mAb products in many companies prioritise commercialisation in more resource-limited settings relative to their introduction lucrative markets in high and upper middle-income in the EU and US55,57 (Figure 5, next page). An countries. Only 21 per cent of new products are filed Access to Medicines Foundation report found that broadly in countries identified as having the greatest innovative products are not even registered in need within a year of launch55. Addressing the

20 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 5: Regulatory approval dates for monoclonal antibodies

Country/ Herceptin® Enbrel® Humira® Keytruda® region (trastuzumab) (etanercept) (adalimumab) (pembrolizumab)

US 1998 1998 2002 2014

EU 2000 2000 2003 2015

Brazil 1999 2003 2003 2016

China 2002 2010 2011 2018

Egypt 2002 No data 2010 2016

India 2000 2002 No data 2016

Mexico No data 2001 No data 2016

South Africa 2001 2004 2006 2017

Zimbabwe 2014 Not Not Not registered registered registered

Source: IAVI registration analysis

barriers to wider registration of mAbs in LMICs is a the number mAbs approved annually. By early priority given the number of products in development 2019, the CFDA had already approved three for diseases that predominantly affect individuals in mAbs from domestic developers and 10 mAbs low-income settings. from multinational pharmaceutical companies, a significant increase from the average two mAbs Harmonising the registration process is one way to approved in previous years60. accomplish this. Regulatory requirements are often unclear or even undefined (seeAppendix , page Some multinational companies are also attempting 38) in many LMICs, and variation in requirements to address delays in access. Novartis and Takeda across national medicines regulatory authorities have launched strategies to make their mAb (NMRAs) increases the cost, time and complexity for products more widely available sooner after their manufacturers interested in submitting their products introduction in high-income countries. For example, for regulatory review58.* Novartis’s mAb Lucentis® for wet age-related macular degeneration was approved in India and Capacity constraints pose an additional challenge. Brazil within 12 months of approval in the EU57. Globally, the WHO estimates that at least 30 per cent of NMRAs have limited capacity to perform Another example is Novartis’s approach to core regulatory functions59. This gap is the widest addressing sickle cell disease (SCD). SCD is a global in Africa, where the majority of the continent’s 50 health problem but the highest burden of disease NMRAs are unable to perform core functions. In is in Africa, where 50 per cent to 90 per cent of Kenya, the Pharmacy and Poisons Board lacks the children born with the disease die before age five61. in-house expertise to evaluate mAbs and therefore Novartis submitted hydroxyurea, the only USFDA- regulatory review must be outsourced.** and EMA-approved drug for the treatment of SCD, to regulators in Ghana, Kenya, Uganda and Tanzania Some countries are taking steps to shorten their to accelerate access to treatment in communities regulatory review timelines. The Chinese Food and that are most affected and plans to deliver 60,000 Drug Administration (CFDA) joined the International treatments by the end of 2020. The company Council for Harmonisation in 2017 and has begun also plans to file its USFDA-approved SCD mAb to align its regulatory processes with international Adakveo®/crizanlizumab globally62 and clinical trials standards, resulting in a dramatic increase in are expected to start in Africa in 2020.***

*Consultation with Utrecht Centre for Affordable Biotherapeutics. 9 August 2019. Phone interview conducted by IAVI. Consultation with African Vaccine Manufacturing Initiative. 3 July 2010. Phone interview conducted by IAVI. **Consultation with Kenyan Pharmacy and Poisons Board. 17 July 2019. In-person interview conducted by IAVI. ***Consultation with Novartis conducted by IAVI. July 2020

21 | Expanding access to monoclonal antibody-based products availability + affordability = access

In addition, the company has signed agreements by the South African Health Products Regulatory with the governments of Ghana, Kenya, Uganda and Authority67. The introduction of mAbs in India is Tanzania to jointly develop holistic approaches to delayed an average of five years19, even though improve the diagnosis, management and effective biosimilar development there is typically faster than care for SCD patients. in high-income countries, taking only three to five years compared to eight years in Europe68. Some Despite these efforts, there are still long delays or middle-income countries such as Mexico, Nigeria complications to broad registration of innovative and Vietnam still require in-country clinical trial medicines and biosimilars in low-income settings. data for regulatory approval or have undefined Even the definition of a biosimilar varies or remains regulations, both of which contribute to delays in undefined in many countries. access64–66.

The EMA first established biosimilar guidelines Addressing these delays and promoting wider in 2005, followed by the introduction of global registration of innovative and biosimilar medicines guidelines through the WHO in 2009, as well as in is therefore essential. This report explores three other countries: Japan (2009), South Korea (2009), potential solutions to expanding the global Canada (2010), the US (2012) and India (2012) have availability of mAbs: all established processes for biosimilar approval63,65. But many LMICs still lack a clear pathway for • harmonise and expand existing policy and registering biosimilars66. Even the BRICS-TM regulatory pathways and explore new ways to (Brazil, Russia, India, China, South Africa, Turkey encourage wider registration of mAbs in LMICs and Mexico) nations have less-defined regulations for biosimilar development and comparability (see • raise awareness of the clinical, public health Appendix, page 38). and economic value of mAbs through concerted advocacy efforts As a result, biosimilar approval and introduction can be delayed even beyond the lengthy timeframe it • strengthen healthcare systems and the ability takes to develop these more complicated products. to diagnose disease in LMICs to support a more The first biosimilar drug approved in South Africa, accurate assessment of the market need for mAb Teva’s Filgrastim®, was delayed more than five years products and to enable their implementation. due to the backlog of products awaiting scrutiny

Harmonising regulatory pathways

There are already some pathways in place to Only WHO prequalification has been used for facilitate broader registrations of both innovative and biosimilar mAbs, and only one mAb has been biosimilar products in LMICs. These programmes prequalified to date. include the WHO’s prequalification programme, the EMA Article 58 pathway, Swissmedic and The WHO prequalification system was originally the US President’s Emergency Plan for AIDS set up to facilitate access to UN-supported health Relief (PEPFAR) tentative approval (Figure 6, next commodities and to address the lack of regulatory page). Prequalification has been used primarily for capacity in resource-limited settings. This generic drugs and biosimilars, whereas the other programme aims to ensure the quality, safety and programmes are designed to accelerate access efficacy of priority global health products, while to innovative medicines. Each of these efforts are supporting capacity building for national regulatory designed to harmonise regulatory procedures and bodies and facilitating access pathways. The first to help manufacturers overcome the barriers to mAb—a trastuzumab biosimilar for the treatment registering their products in LMICs that may lack of breast cancer—was prequalified in 2019 clear regulatory processes. through a pilot procedure developed in 201883,230. Prequalification of the biosimilar rituximab for the But so far these programmes have not been treatment of common lymphomas and leukemias extensively utilised to facilitate access to mAbs. is underway.

22 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 6: Collaborative and expedited regulatory pathways Regulatory Pathways Potential applications agencies/bodies to antibody products

USFDA FDA’s expedited review of PEPFAR’s innovative HIV products in as HIV bnAbs short as 6 months and tentative approval of generics for sale outside the US for HIV products still under US market exclusivity.70

USFDA, WHO, Collaborative Registration Procedure-Lite (CRP-Lite): facilitated HIV bnAbs NRAs through sharing of redacted assessment reports of FDA-approved products with WHO to accelerate registration of HIV medicines in low- and middle-income countries71

EMA, WHO, Article 58: EMA, in collaboration with the WHO, provides scientific Monoclonal antibodies NRAs opinions on medicines to prevent or treat diseases of major public for infectious/neglected health interest that are intended exclusively or initially for markets diseases mainly in outside the EU72 low- and middle- income countries

EMA, WHO, Parallel EU and low- and middle-income country registrations: Monoclonal antibodies NRAs A promising initiative through which EMA collaborates with sponsors for global health on a parallel approach that integrates elements of the Article 58 process, such as representation from WHO and low- and middle- income country NRAs during the assessment process, as part of a centralised Marketing Authorisation Application for EU registration. This pathway was tested with the recently licenced Ebola vaccine (ERVEBO®).*

Swissmedic, Swissmedic (Switzerland) authorisation procedures involve African Monoclonal antibodies WHO, NRAs NRAs and WHO in the assessment process, building capacity and for global health addressing regional considerations while accelerating marketing authorisations in Switzerland for Africa and elsewhere73

*Consultation with EMA. 20 September 2019. Phone interview conducted by IAVI

To address some of the barriers to access that exist Efforts to speed approval timelines for innovative even after prequalification, the WHO also developed products are therefore underway through the a collaborative registration process (Figure 6) with Accelerated Registration of Finished Pharmaceutical stringent regulatory authorities (SRAs) to accelerate Products Approved by SRAs procedure. Through national registration of WHO-prequalified products. this procedure, the assessment and inspection More than 20 African national regulatory authorities reports of participating reference SRAs — EMA, (NRAs) participate in WHO collaborative registration Swissmedic, the UK Medicines and Healthcare schemes, and these have resulted in registration of Products Regulatory Agency and the Swedish 152 essential medicines, cutting assessment and Medical Products Agency — and bridging reports approval time from several years to an average of that address issues of direct relevance in high- 78 days69. Now that a trastuzumab biosimilar is burden settings are shared with NRAs in 21 prequalified, it is eligible for collaborative registration. participating countries and the Caribbean nations Most stakeholders from the African continent who in the CARICOM region. The goal is to facilitate were interviewed for this report agreed that products national regulatory decisions within 90 days75. This prequalified by the WHO or approved by an SRA procedure has resulted in 42 regulatory approvals such as the EMA or the USFDA would be more likely for five different products in 20 countries, but has to be licensed quickly in their countries. not yet been utilized for mAb products. Many other challenges also remain, including addressing Yet even with prequalification and collaborative inconsistent requirements across NRAs that required registration processes, some stakeholders report supplemental documentation and additional there are still delays in access to innovative inspections. medicines. A 2016 study showed that vaccines already approved by an SRA still took on average One effort to support regional harmonization of NRAs 16 months to complete the prequalification is the African Medicines Agency (AMA). In 2019, 55 process74. Generic medicines from emerging African nations signed the treaty to form the AMA, markets took even longer—more than two years which will promote the adoption and harmonisation on average. of regulatory policies and standards and will

23 | Expanding access to monoclonal antibody-based products availability + affordability = access

coordinate existing harmonisation efforts76. The aim Funders such as the Bill & Melinda Gates Foundation of the AMA is to align fragmented regulatory systems and Unitaid are also supporting efforts to facilitate on the continent, reduce the lead time associated regulatory approvals of priority global health with meeting different country requirements and products in LMICs. Unitaid is supporting efforts increase the availability of safe, effective and high- to ensure that innovative biologics are promptly quality essential medicines for priority and neglected produced and accessible in LMICs. They are diseases across the African continent77. The AMA partnering with the WHO, UN agencies and product will provide an important platform to address developers to support prequalification and to some of the regulatory barriers impeding access to allow for rapid scale-up of high-quality, affordable biologicals in Africa78. biologics in these countries.* These efforts will be particularly important for countries that eventually Another effort to support harmonisation is the African transition from receiving assistance from global Vaccine Regulatory Forum (AVAREF), a regional health organisations such as The Global Fund, to a regulatory network founded by the WHO in 2006 reliance on domestic funding. with 23 African member-countries. AVAREF aims to support NRAs in their decision making by providing Additional efforts to harmonise registration pathways information on vaccine candidates and timelines for for mAbs in LMICs may also be required to ensure clinical trials, and also to promote communication broad availability of these products in developing and collaboration between African NRAs and ethics countries. committees79. Although only applicable to vaccines, AVAREF could be a model for supporting regional NRAs for mAb regulatory issues.

Expand and utilise policy pathways for mAb access

WHO policy guidance also plays an important product profiles based on the needs of individuals in role in the adoption of new technologies and their high-income countries. This can result in products integration into financing and procurement platforms. that are not as well suited for use in LMICs because Some stakeholders that were interviewed noted of factors such as their dosing regimen, side effects that many LMICs will not include a medicine on or feasibility constraints81. To avoid this, the WHO is their national medicine lists or utilise a treatment or developing PPCs to provide strategic guidance on the therapy unless it is part of WHO guidelines.** preferred attributes for new vaccines and antibodies in priority disease areas. PPCs are developed as It can therefore be beneficial for mAb developers to part of a broad consultation process early in clinical engage with the WHO early in the process if they are development. Considering the needs of individuals interested in having their products included in WHO outside of high-income countries early in the mAb policy guidelines and securing prequalification. This development process—when product attributes engagement allows the WHO to provide guidance can be more readily changed—can help ensure that on the preferred attributes of an eventual product products satisfy end-user preferences and pricing as well as its potential value proposition and access expectations, and that they can be implemented in pathways, all of which can help favorably position places with more limited healthcare infrastructure. products for a policy review that occurs post licensure80. Technology Roadmaps and Full Public Health Value Propositions: Preferred Product Characteristics (PPCs): Technical documents such as these outline priority Most companies that develop mAbs design target activities for researchers, funders and product

*UNITAID consultation. 31 July 2019. Phone interview conducted by IAVI. **Global Fund and PEPFAR consultation. 17 June 2019. Personal interview conducted by IAVI; WHO and UNAIDS consultation. 29 May 2019. Phone interview. Interview conducted by IAVI; UNITAID consultation. 31 July 2019. Phone interview conducted by IAVI.

24 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 7: Monoclonal antibodies included in the WHO Model List of Essential Medicines

Antibody Brand name First approved indication WHO EML inclusion year

Adalimumab Humira® Rheumatoid arthritis 2019

Certolizumab pegol Cimzia® Crohn’s disease 2019

Golimumab Simponi® Rheumatoid and psoriatic arthritis, ankylosing spondylitis 2019

Infliximab Remicade® Crohn’s disease 2019

Nivolumab Opdivo® Melanoma, non-small cell lung cancer 2019

Pembrolizumab Keytruda® Melanoma 2019

Rituximab MabThera® Non-Hodgkin’s lymphoma 2015 Rituxan®

Trastuzumab Herceptin® Breast cancer 2015

Bevacizumab Avastin® Colorectal cancer* 2013

*WHO EML for age-related macular degeneration, not licensed for this use. Source: WHO (2019) Model List of Essential Medicines

developers to accelerate the availability of The growing number of mAbs on the EML is products in priority disease areas and to articulate spurring efforts within the WHO, relevant UN the economic, societal and indirect impact of the agencies and international organisations to intervention at the population level. facilitate access to these products83. Inclusion of mAbs on the EML should encourage more Together, these guidance documents can facilitate countries to add them to their own essential the inclusion of a mAb product in formal WHO medicine lists—more than 155 countries create guidelines80. This approach is primarily used national essential medicines lists based on the for development of new vaccines, but in recent EML38. years the WHO has provided some preliminary guidance on preventative mAbs for RSV and However, delays are still likely as national lists may rabies in the context of available vaccines, and not be updated as regularly. Kenya first established the organisation is now involved in drafting the its essential medicines list in 1981, but has only first formal PPCs for HIV and RSV mAb products. updated it four times since then84. Despite Avastin’s inclusion on the EML in 2013, and Herceptin and Adding mAbs to the WHO’s Model List of Rituxan being added in 2015, there is limited Essential Medicines (EML) is another way to evidence that these mAbs are widely included on influence national policies and encourage broader national medicine lists and therefore the impact on uptake of mAbs. Inclusion on the EML can affect global access is unclear85. Addressing the barriers eligibility for reimbursement through public health (including patent protection and registration) systems82, and can help ensure these products to nations adding mAbs on the WHO EML to are integrated into procurement and supply their own essential medicine lists will help raise channels. awareness of the value of mAbs and enhance access in LMICs. Avastin® (bevacizumab) was the first mAb added to the EML in 2013 for off-label treatment of age- In addition to the EML and other WHO policy related macular degeneration (Figure 7). In 2015, pathways, health technology assessment (HTA) Rituxan® (rituximab) and Herceptin® (trastuzumab) bodies that perform value-based assessments of became the first two cancer mAbs to be added innovative medicines and help determine pricing to the EML. These mAbs were added long after (see page 30) could also be used to influence their initial approval, but in the last two years, 18 which mAbs are included on national medicine antibodies were reviewed and six were added to lists. HTAs in some LMICs such as China, Thailand the EML in 2019 alone.* and Tanzania are already being utilised this way86–88.

*WHO and UNAIDS consultation. 29 May 2019. Phone interview conducted by IAVI.

25 | Expanding access to monoclonal antibody-based products availability + affordability = access

Raise awareness of the health benefits of mAbs

Advocacy is essential to promoting supportive Cost-effectiveness and health economic policy regarding mAbs and to enhance availability. modelling of the impact of mAbs can also Yet advocacy for mAb products is either limited help inform advocacy efforts by establishing or nonexistent. The unprecedented advocacy that a value proposition for introducing mAbs played a vital role in expanding access to HIV more broadly, particularly within the public medicines and preventives in developing countries health systems of LMICs. For cancer, mAb could serve as a model. A similar movement could products could even be introduced before help bolster the case for global mAb access. older medical options, “leapfrogging” radiation treatment and chemotherapy, which are more Underpinning all efforts to make mAbs more widely challenging to implement in resource-poor available is the need to increase awareness among settings89. governments, ministries of health and patient advocacy groups of their transformative health Another component of advocacy for mAb benefits, both on the individual level and the public access is ensuring that mAbs receive health level. As governments struggle to prioritise widespread support through their inclusion healthcare interventions, advocacy efforts will be in UN-backed global public health agendas, critical to making political leaders and public health such as the Sustainable Development Goals officials aware of the broad potential mAbs offer to and Universal Health Coverage (UHC). UHC, treat and prevent diseases. which was adopted in 2015, calls for all individuals and communities to receive health Related to this, advocacy efforts could help dispel services without suffering financial hardship. the misperception that mAbs are too expensive Including mAbs in such agendas can spur to ever become widely available in LMICs. Some government investment and stimulate industry mAbs are already available at much lower prices, focus on delivering affordable and accessible and by implementing a combination of innovative mAb products. Major public health funders, technologies and alternative business models (see including Wellcome through their Flagship page 28), these prices could be even lower, making initiative, the Bill & Melinda Gates Foundation, them more affordable for more of the world. Global Unitaid and the Coalition for Epidemic access to mAbs will not be easy, but it is possible, Preparedness Innovations (CEPI) are either and advocacy efforts will be required to deliver that already considering or could consider adding message. mAb development to their portfolios.

Strengthen healthcare systems and the ability to diagnose disease

Improving capabilities to both diagnose and treat disease is another important component of In many countries improving global access to mAbs. there are not enough Gaps in local health systems and inadequate infrastructure hamper the delivery of medicines to specialists, experts millions of people and delay access to innovative medicines such as mAbs. or specialised

This is particularly true for products to treat non- communicable diseases. Most deaths from non- medical centers communicable diseases occur in LMICs, where 85 per cent of the global population lives25,26. for specific diseases. Cancer services and access to diagnostic medical equipment are limited in these countries (Figure 8, next page) despite a large and growing disease

26 | Expanding access to monoclonal antibody-based products availability + affordability = access

burden. In many countries there are not enough specialists and/or specialised medical centers Figure 8: Pieces of medical equipment for specific diseases90. For example, Zambian per million population in 2013 cancer patients must travel to South Africa Country Magnetic Radiation and pay out of pocket to access mAb cancer resonance therapy treatments, an option only viable to wealthy imaging individuals.* Japan 45.94 7.17

The burden of many diseases is also unknown or Canada 7.99 8.07 measured inaccurately in many LMICs, including Mexico 1.41 0.54 Kenya and Zambia, because of limited medical staff, training and diagnostic equipment90,91,99. Yemen 1.15 0.12 Strengthening healthcare systems and the ability Honduras 1.11 0.74 to diagnose disease will help provide mAb Zimbabwe 0.28 0.42 manufacturers with a more accurate assessment of disease burden and the market size for their Afghanistan 0.10 0.00 products in LMICs, which is a critical component Uganda 0.08 0.05 of expanding access to mAbs. Cambodia 0.07 0.07

For infectious diseases, expanding the Zambia 0.07 0.04 availability and rapid use of diagnostic tests Central African Republic 0.00 0.00 confirming the type and strain of pathogen is also critical to ensuring timely and appropriate Source: WHO (2016) Global Health Observatory data repository treatment. To enable broader use of therapeutic mAbs, diagnostic capabilities for infectious diseases will also need to be strengthened.

*Personal communication with Professor Chipeta at the University of Zambia and IAVI

27 | Expanding access to monoclonal antibody-based products Making monoclonal antibodies more affordable

Key findings: mAbs are unaffordable for most of the world’s population.

Companies focused on high-income country markets have little incentive to pursue lower-cost strategies to develop, manufacture and deliver mAbs.

Competition, regulation and other strategies that can lower mAb prices are not sufficient to make these products affordable globally.

Advancements in antibody optimisation, manufacturing technologies and packaging and delivery have the potential to lower mAb production costs and increase efficiency.

Local and mobile manufacturing of mAbs are untested in LMICs but may be an alternative for improving access to affordable mAbs in remote areas.

Creative intellectual property/licensing frameworks may help expand access to mAbs.

Alternate business models, including public-private partnerships and industry-led access models, are emerging to support mAb research and development, manufacturing and global access for non-communicable and infectious/neglected diseases.

Including mAbs in pooled procurement platforms, similar to those used for vaccines, could make them more widely accessible.

One barrier to achieving global access approximately $100,000 higher than mAbs for other to innovative mAbs is that they are diseases94,95. unaffordable for most of the world’s population. Drug prices, including those for mAbs, vary greatly worldwide because of a variety of factors (see page Biologics, and particularly mAbs, are among 30). But with few exceptions, existing price-control the highest priced pharmaceutical products mechanisms and access strategies are insufficient in the world7. In the US, biologic drugs to make mAbs widely affordable (Figure 10, next represented 2 per cent of all prescriptions in page). 2017, but 37 per cent of net drug spending93. The median price for mAb treatments in the The same is true for biosimilars. The introduction of US ranges from approximately $15,000- lower-priced biosimilar mAbs can offer significant $200,000 a year31 (Figure 9, next page). savings to payers and governments that are And mAb-based therapies are increasingly struggling to prioritise healthcare interventions prescribed in sequence or in combination, and manage already stretched budgets. But, which can result in even higher treatment to date, biosimilars have not expanded access costs. substantially. This is because they are still largely unaffordable53,100. The most expensive mAbs are for oncology and hematology, with annual treatment prices In most countries, generic drugs are typically sold

28 | Expanding access to monoclonal antibody-based products availability + affordability = access

at steep discounts—more than 90 per cent off the Figure 9: Median price of monoclonal original price—whereas biosimilars are generally antibodies by therapy area only 10 per cent to 35 per cent less expensive than the originator mAb in most countries. This for one year of treatment difference is explained, at least in part, by the fact US prices as of January 2017, in US dollars that biosimilars are much more complicated and costlier to develop than small molecule generics Oncology/hematology (see page 13). $142,833 Immunology Even in India, where biosimilar prices are $52,969 discounted the most because of extensive local production and competition among Infectious diseases/allergy biosimilar manufacturers, they are discounted $29,808 by 57 per cent—significantly less than generic Ophthalmology drug discounts14,31,57,101. $22,464

The WHO estimates that up to 90 per cent of the Cardiology/endocrinology population in LMICs purchase medicines through $15,624 out-of-pocket payments102. Therefore, even at a substantial discount, mAbs and biosimilars 0 40,000 80,000 120,000 $160,000 remain too expensive for many people. Also, few, if any, of the most commonly prescribed mAbs are Source: Hernandez (2018) Am J Manag Care reimbursed through public health systems even in some middle-income countries, such as Kenya, India and Egypt (Figure 10)56,96,97,103.

This report focuses on three potential solutions, • implement alternate business models that which if applied in combination, could make mAbs prioritise access more affordable: • identify procurement and delivery models for • validate and apply novel technologies to lower mAbs similar to those used to increase access mAb development and manufacturing costs to vaccines.

Figure 10: Availability of seven monoclonal antibodies* in selected countries with different levels of universal health coverage, 2018

Available, reimbursed/on national list Available, not publicly reimbursed

7 7 1 3 3 5 No 7 7 data 6 6 Not avail. 5 No 4 data 4 4 4 3

2 2 2 1 1 0 UK Sweden Brazil Mexico China Morocco Kenya India Egypt

High-income countries Upper-middle income countries Lower-middle income countries

*Adalimumab, cetuximab, ipilimumab, panitumumab, pertuzumab, rituximab, trastuzumab. Note: “not avail.” = not available/not registered Source: WHO (2018) Pricing of cancer medicines and its impacts

29 | Expanding access to monoclonal antibody-based products availability + affordability = access

Factors influencing global mAb prices

Several factors influence drug prices, and how they are applied varies in different parts of the world. As a result, drug prices can also vary widely (Figure 11, next page). Some of the most common factors that affect global mAb prices are:

1 COMPETITION among products for similar Spain and Italy, autonomous regions and hospitals indications or with similar mechanisms of action sometimes conduct their own HTA and negotiations can impact price, as can competition from with manufacturers after national decisions, leading biosimilars. to further delays107,108.

Competition in the Indian biosimilar market has led Risk-sharing agreements between the payer and a to biosimilars that are priced up to 70 per cent lower company can also be used when there is uncertainty than the local retail price of the innovator mAb. In associated with the efficacy of a drug. Risk-sharing some cases, biosimilar competition can even spur agreements allow payments to be determined manufacturers to lower the price of the originator based on the clinical benefit of a product. Risk- antibody to retain market share. Dr. Reddy’s sharing agreements have improved access to select Laboratories biosimilar Reditux® (rituximab) was medicines in some European countries, including introduced in India at 50 per cent less than the retail Sweden, Portugal and Italy109,110. price of Roche’s Rituxan/MabThera® (rituximab)104. In response, Roche lowered the price of Rituxan® to More than 25 European countries have a national promote its brand-name product104. HTA and the Japanese government recently announced plans to implement one111,112.

INTERNATIONAL REFERENCE PRICING Efforts to establish HTA-like groups are also 2 (IRP) is one of the most common price-control emerging in some African countries. With the support mechanisms used by governments. It uses the of the International Decision Support Initiative, the proposed price of a product in several countries KEMRI-Wellcome Trust Research Programme is to derive a benchmark or reference price. supporting the development of an HTA mechanism in Kenya. Most participants in stakeholder meetings The potential downside of IRP is that it may cause convened in Zambia, Uganda, Kenya and South companies to delay or avoid launching new drugs Africa agreed that establishing HTA bodies to assess in countries that use IRP, especially if they are small mAbs would be useful; however, they cautioned markets referenced by countries with larger markets. that there may not be enough skilled personnel to One study showed that pharmaceutical companies form these advisory bodies, especially in smaller systematically delayed submission in Belgium African countries. As an alternative, they suggested because of IRP105. establishing more regional HTAs that could evaluate data from countries with similar disease burdens and demographics. 3 COST-EFFECTIVENESS THRESHOLDS are used to determine the acceptable price 4 TIERED PRICING is a strategy used to set based on a product’s clinical effectiveness. prices for different parts of the world based on macroeconomic indicators, such as the average Health technology assessment (HTA) mechanisms national gross domestic product per capita. are increasingly used to make value-based Tiered-pricing levels are often established assessments of medicines and to inform both pricing through direct negotiations between government and reimbursement decisions. HTAs are usually payers and manufacturers. conducted by independent government agencies such as the National Institute for Health and Care Tiered-pricing arrangements vary across companies, Excellence in England, the Canadian Agency for therapy areas and products. They are currently being Drugs and Technologies in Health or the National applied in Kenya to increase patient access and Committee for Health Technology Incorporation affordability to Roche’s cancer mAb trastuzumab113. (CONITEC) in Brazil. One drawback to HTAs is In 2016 Roche agreed to provide trastuzumab to that they are time-consuming processes that can the Kenyan government at 50 per cent off its normal delay patient access, particularly for products that price. The Kenyan government then agreed to receive conditional regulatory approval based on establish a small fund (initially valued at $195,000) to limited clinical data106. And in some countries, like help patients pay the remaining treatment costs114.

30 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 11: International comparison of Herceptin® (trastuzumab) prices

Price per dose of 2 mg/kg for a 75 kg patient, in US dollars $2,000

1,600

1,200

800

400

0

Herceptin® Kanjinti® Herceptin® Herceptin® Kanjinti® Herceptin® Herclon® Herclon® CanMab® (biosimilar) (biosimilar) (2nd brand) (2nd brand) (biosimilar)

United States China United Kingdom South Africa India

Sources: 28–32

This programme is attempting to make a cancer mAb markets. Introducing second brands can also more affordable in a country where 75 per cent of the increase competition. population lacks private health insurance115. In some cases, second brand strategies and 5 DIRECT PRICE NEGOTIATIONS between alternate supply chains have led to more affordable pharmaceutical companies and governments or mAb prices in middle-income countries. In procurement bodies can provide assurance of South Africa, Roche sells its breast cancer mAb significant market volume, which ultimately can trastuzumab as both Herceptin®, the original brand, be an incentive for manufacturers to lower their and as a second brand called Herclon®. Herclon® is prices. sold for $145 per dose—a 70 per cent discount off the price of Herceptin®—and is only available within China is increasingly relying on direct price the public health system28. In India, Roche only negotiations to determine drug prices for national sells the lower-priced, second brand Herclon®. This reimbursement116. The National Development has given rise to increased biosimilar competition. and Reform Commission now sets a maximum The biosimilar CanMab®, manufactured by the reimbursement for products on the National Indian company Biocon, is available in India at a Reimbursement Drug List (NRDL). Only those products substantially lower price than Herclon® (Figure 11). included on the NRDL are eligible for provincial tenders. Manufacturers are therefore incentivised to In India, Roche partnered with the local manufacturer lower prices to be included on the NRDL, and then Emcure to produce and market second brand to lower prices even further to win provincial tenders. versions of two of their mAbs: Herclon® and Trastuzumab was launched in China in 2002 and Mabthera®, a second brand of Rituximab® 118. Roche reduced the price of the mAb by roughly 70 per cent to get it included on the NRDL in 201729,117. In many instances, these pricing factors are INTRODUCTION OF SECOND BRANDS is a applied in an integrated manner. In Brazil, for 6 way for companies to market lower-priced versions example, regulators use both IRP and value-based of an originator mAb in a specific market, such as assessments based on advice from the national HTA public health systems in LMICs. agency CONITEC119. A manufacturer must prove that a new medicine offers clinical benefits over a Second brands have a different name and use unique comparator to be able to charge a premium price. supply chains, sometimes including the use of local If deemed innovative, IRP is then used to derive manufacturers, to further differentiate them from the drug’s list price. The average price of the mAb original brands and to prevent lower-priced products trastuzumab dropped by 57 per cent after it received from threatening profitability in high-income country CONITEC approval in 2012120.

31 | Expanding access to monoclonal antibody-based products availability + affordability = access

Validate and apply novel technologies to lower costs

The process of developing new medicines is long antibodies from currently or previously infected and costly. It’s reported to cost on average humans—that bind to specific targets. $2.6 billion to develop a new drug121, although the precise costs associated with developing any Technological advances are also making it possible specific product are undisclosed. Pharmaceutical to engineer mAbs to improve their potency, breadth, R&D is also a high-risk business as many drug and half-life and biophysical properties5,124. For example, vaccine candidates fail in clinical testing. clinical studies of the anti-RSV antibody MED18897- YTE and the anti-HIV antibody VRCO1-LS have In the US, where prescription drug prices are the demonstrated that slight modifications can lead to highest, there is no clear association between four- to fivefold enhancements in half-life, which is research and development costs and drug prices122. anticipated to translate into products that can be Companies that market many of the originator delivered less frequently, on average once every mAbs are primarily focused on markets in high- three to six months5,124. More recently, an integrated income countries, where prices are the highest. approach of deep sequencing, bioinformatics and Given this, there is limited incentive for companies directed evolution by yeast display is being utilised to devise lower cost strategies for developing or to select and optimise antibodies with biophysical manufacturing mAbs in an effort to lower prices123. characteristics that would make them more amenable to manufacturing125. It reportedly costs between $95–$200/gram to produce marketed mAbs, with even higher costs For example, Just Biotherapeutics, which was for startup companies, and this does not take recently acquired by Evotech Inc., uses software into account research and development costs14. to predict how modifying the DNA sequence of a However, there are several innovative technologies protein could increase its drug-like properties and that could be applied across the mAb development expression in cell culture, thereby making it easier continuum—from discovery to delivery—which, to purify and manufacture. The company, with if coupled with alternate business models, could support from the Bill & Melinda Gates Foundation, is substantially reduce mAb development and developing their technology to develop sequence- production costs as well as prices. optimised broadly neutralising HIV mAbs with improved stability that could be manufactured at low cost126. Selection and optimisation

Advances in B-cell immortalisation, high-throughput Manufacturing screening, single-cell analysis and display technologies, and humanised animal models (see Currently, most commercial mAbs are produced Appendix, page 34) have made it possible to rapidly in mammalian Chinese Hamster Ovary (CHO) cells identify antibodies—including rare and potent that are engineered to produce a large quantity of

“Improvements in mAb potency and reduced manufacturing costs would reduce the dosage and frequency of administration, leading to decreased cost and improved convenience.”

Gary Nabel, CSO and Senior Vice-President, Sanofi Inc.

32 | Expanding access to monoclonal antibody-based products availability + affordability = access

antibodies (in the 1–5 gram/liter range)123. CHO cell runs the world’s largest disposable bioreactor-based lines expressing the antibody of interest are typically biologics manufacturing facility. The facility uses grown in large bioreactors for more than 10–15 days. a continuous bioprocess system integrated with The resulting antibodies are then purified through single-use bioreactors that is predicted to reduce multiple-column chromatography methods127 and mAb manufacturing costs from $95–$200 per gram formulated for appropriate administration, a process to less than $15 per gram, or $3 for an average called “batch production.” CHO cells make fully 200 mg dose of most mAbs130–132. If these efforts to functional proteins that are generally well tolerated dramatically lower production costs are coupled with by humans, but they require a long production time a dramatic reduction in price, it would be a big step and high material costs. towards making mAbs more affordable.

To reduce cost and increase capacity, many The Serum Institute of India is also investing in manufacturers are therefore exploring alternatives more efficient manufacturing processes with to batch production methods. Continuous multiple modular facility units at a new site in Pune, biomanufacturing and single-use bioreactors are India, to support their growing investments in both two technologies that can improve the speed, biosimilar and innovative mAb development and flexibility and convenience of CHO-based mAb manufacturing133. production128. Single-use bioreactors allow for a quicker turnaround, can be used in tandem to Many alternatives to CHO-based mAb production produce biopharmaceuticals at scale and require are also being explored134 (Figure 12). Alternate significantly lower capital investment to construct. production platforms, including yeast, fungus, algae This technology has enabled the development of and transgenic plants, as well as nucleic acid delivery global mAb production facilities. via DNA or messenger RNA (mRNA; Figure 13, page 35) have the potential to be cheaper and faster than Integrated continuous biomanufacturing processes traditional methods. Using genetic constructs—either are also faster and cheaper129, and offer more DNA or mRNA—as a delivery system could reduce consistent processing and greater product quality. production costs by five- to tenfold135. Economic analyses of continuous biomanufacturing coupled with continuous chromatographic processes (referred to as integrated continuous processing) Packaging and delivery can reduce costs by 55 per cent compared to conventional batch processing, considering both The way mAb products are packaged and delivered capital and operating expenses128. can also help lower mAb production costs. Delivery of mAbs is complicated by their physiochemical and WuXi, a leading mAb manufacturer based in China, biological properties. Most antibodies are delivered

Figure 12: Alternative monoclonal antibody manufacturing methods

Method Manufacturer Programmes Highest status Advantages of programmes and challenges

Yeast Alder Migraine and Submitted Lower upfront investments and lower Biopharmaceuticals chronic to USFDA for cost of production; glycosylation autoimmune approval patterns and post translational diseases modifications can be a challenge; however, GlycoFi engineered strains Research Contract Available for more human-like — but no recent Corporation work licence activity reported136,137 Technologies

GlycoFi (Merck) Unreported

Numerous groups Preclinical in research: Genomics Research Center; Academia Sinica Taiwan; Scripps Research; MIT

(table continues on next page)

33 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 12: Alternative monoclonal antibody manufacturing methods (continued)

Method Manufacturer Programmes Highest status Advantages of programmes and challenges

Transgenic Mapp Ebola, HIV Phase II Lower upfront investments as tobacco Biopharmaceutical; smaller facilities needed, but LeafBio variation in quality138–140

PlantForm Cancer, Ebola Preclinical HIV, ricin, undisclosed

Planet Common Discontinued Biotechnology Inc. cold Phase II

Fraunhofer HIV Phase I Institute for Molecular Biology

iBio RSV, Ebola Preclinical

Fungus Dyadic with Serum Undisclosed Undisclosed Higher yield per liter of media and Institute of India potential for lower cost; engineering of more human-like strains ongoing141

Milk of China Agricultural Cancer Preclinical Lower upfront investments but transgenic University glycosylation challenges142 cattle

In vitro Sutro Biopharma Cancer Preclinical Potential for lower cost; however, cell-free large-scale production untested143 expression systems

Algae Institut de Hepatitis B Preclinical Low production costs; challenges Recherche et with heterogeneity and d’Innovation post-translational modification144–147 Biomédicale

Scripps Research; Cancer, Preclinical University of anthrax, HSV, California, botulism San Diego

Algal Research No mAb data Group; University College London

Baculoviral Vienna Institute of HIV Preclinical Potential for lower cost; however, insect cell Biotechnology; large-scale production untested148 University of Natural Resources and Life Sciences

Silkworm National Institute Cancer Preclinical Potential for lower cost; however, baculovirus of Health Sciences, large-scale production untested151 expression Kanagawa

Drosophila Institut Pasteur of Influenza Preclinical Potential for lower cost; however, S2 cell line Shanghai large-scale production untested149

In situ IAVI HIV Phase I Potential for lower cost; however, vector gene undetectable expression in clinical delivery study (lack of proof of concept)150

NIAID HIV Phase I Ongoing POC (NCT03374202)

Table doesn’t include data for SARS-CoV-2 mAbs

34 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 13: DNA and mRNA monoclonal antibody delivery

Target Antibody Organisation mRNA clinical Emerging diseases Chikungunya virus mAb ModernaTX First in class Phase I NCT03829384 mRNA preclinical Oncology Lymphoblastic leukemia mAbs and bispecific BioNTech152 T cell engagers

Non-Hodgkin’s lymphoma mAb CureVac AG153

Breast cancer mAbs and bispecific Inovio Pharmaceuticals154 T cell engagers

Infectious diseases HIV mAb University of Pennsylvania155

HIV, influenza B, rabies mAb CureVac AG153

RSV mAb, VHH Emory University156

Toxins Botulism VNA/VHH CureVac AG153

DNA clinical Emerging diseases Zika mAb Inovio Pharmaceuticals First in class Phase I NCT03831503

DNA Preclinical Emerging diseases Ebola (Zaire) mAb Wistar Institute157

Dengue mAb University of Pennsylvania158

Infectious diseases HIV mAb Wistar Institute159

Influenza A and B viruses mAb Wistar Institute160

AMR Pseudomonas aeruginosa mAb Wistar Institute161

VHH = variable domain of heavy-chain-only antibody. VNA = VHH-based neutralizing agents. AMR = antimicrobial-resistant diseases Table doesn’t include data for SARS-CoV-2 mAbs

either intravenously, subcutaneously or in some (Figure 14, page 37). Additional investments and cases through nasal administration if the mAb is innovation are needed to create convenient and susceptible to gut protease degradation. Intravenous affordable devices that are more amenable for (IV) administration has several drawbacks: it is more global use. complicated, it can be more painful and therefore less tolerable for recipients, and it is more expensive Technologies that enable oral delivery of mAbs are as it must be administered by a medical professional. also in development. Most mAbs are of the naturally Studies have found that IV administration of occurring immunoglobulin G (IgG) subtype1. This trastuzumab is associated with a more than twofold subtype of mAbs is relatively stable and has long higher administration cost (not including the cost of half-lives, which makes it suitable for large-scale the mAb)164. manufacturing. But the naturally occurring IgA2 mAb subtype is resistant to mucosal proteases and Alternate administration routes are therefore one way enzymes, making them amenable to oral delivery. to reduce delivery costs. Subcutaneous injection is a In preclinical murine challenge studies, oral delivery less expensive way to administer mAbs. About one- of IgA2 mAbs protected against enteric bacteria third of all mAbs approved in the past ten years are including Salmonella, Shigella and E. coli166,167. administered via subcutaneous injection165. These IgA2 mAbs have shorter half-lives and are more challenging to manufacture168, so new Some manufacturers are also researching more technologies are being developed to address these patient-friendly and cost-effective delivery devices, shortcomings. For example, heavy-chain variable including microneedles and slow-release implants domain nanobodies that are engineered to be

35 | Expanding access to monoclonal antibody-based products availability + affordability = access

resistant to intestinal and inflammatory proteases have been delivered orally and shown to survive in Mobile manufacturing the intestinal tract of humans with intestinal bowel disease169, 170. More flexible and modular units are also being For more, see the supplement to this report: developed to manufacture biologics. These Combination monoclonal antibodies mobile manufacturing units could be particularly and alternate formats useful in local outbreak situations. However, these technologies have not yet been tested or used for the local production of quality-controlled, affordable A proprietary spirulina algae-based production biologics in an LMIC setting. and oral delivery technology is also being tested in preclinical studies for the delivery of single- • Univercells’s miniaturised bioreactors are easily chain camelid antibodies for diarrheal diseases171. transportable and could enable in-country Researchers are isolating antibodies from humans mAb production by deploying low-footprint, that could be delivered orally for the treatment of multiproduct facilities that are more affordable to serious diarrhea and intestinal inflammation caused build and operate162. by C. diff infections172. Other technologies that could allow for oral delivery of antibodies for enteric • Emergent BioSolutions Inc. is developing a mobile, and liver diseases are also in development173. small-scale manufacturing site for biologics that is designed to manufacture mAbs in a controlled In addition to the route of administration, innovative environment the size of a shipping container that approaches to packaging and storage can also could be deployed wherever an outbreak occurs163. help make mAbs more affordable. Blow-Fill-Seal technology, a form of advanced aseptic packaging • Research is also advancing in the field of benchtop in which the container is formed, filled and sealed manufacturing. Some groups are developing in one automated system, has recently been used small automated systems capable of producing for injectables and biologics, including vaccines clinical-grade therapeutic proteins, including and mAbs174. Blow-Fill-Seal technology replaces mAbs, in a matter of days. These fast and flexible glass vials or pre-filled syringes—typically used for manufacturing processes could be performed in subcutaneously administered mAbs175—with plastic, a hospital or a pharmacy and could enable the which reduces accidental breakage. The low-cost, production of small amounts of mAbs for endemic aseptic design and compact nature of Blow-Fill- breakouts, with limited, if any, cold chain storage. Seal tubes, which can be custom made for a wide The Massachusetts Institute of Technology (MIT) range of volumes and readily shipped, could help is developing the Integrated Scalable Cyto- achieve broader access to mAbs. Technology, a closed system of producing and purifying biologics using Pichia pastoris yeast Shipping and delivering mAbs is also complicated cells. This platform has the potential to shorten because they are typically less stable at ambient production times by tenfold163. temperatures and therefore require cold storage. Maintaining cold-chain facilities can be challenging in some parts of the world. In Africa, cold-chain systems are primarily used for storing and shipping childhood vaccines and there’s little additional How all of these technologies are applied—whether capacity. Cold-storage systems also add to the it is optimising antibodies to lower the dose, using expense of delivering mAbs, particularly in low- alternate manufacturing platforms or developing oral income countries that contend with frequent formulations—will ultimately determine how much power outages. Products that require freezing lower mAb costs can be. Alternate business models temperatures for transport and storage would will also need to be implemented to ensure that pose a challenge in many countries, according to lower production costs result in lower prices. Other stakeholders. Therefore, technologies that could factors will also need to be considered, including reduce the cost of monitoring and maintaining the disease in question, the existing treatments cold-chain systems* as well as developing alternate available, what is feasible in various LMIC settings thermostable formulations of mAbs that would and what is acceptable to the populations that will enable storage at ambient temperatures could also ultimately use these products. Understanding the help make mAbs more affordable and accessible. preferences of communities, healthcare workers and

*Consultation with Southern African Programme on Access to Medicines and Diagnostics. 17th July 2019. In person interview conducted by IAVI. Consultation with CAPRISA. 19 July 2019. Phone interview conducted by IAVI

36 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 14: Examples of advancements in mAb delivery

Advancement Device or technology Antibodies

Large volume Halozyme ENHANZE: Drug delivery Roche with Halozyme has developed two subcutaneous technology based on recombinant human cancer mAbs; Herceptin Hylecta® delivery hyaluronidase PH20 enzyme, rHuPH20, which (trastuzumab) and Rituxan Hylecta® locally degrades hyaluronan in the (rituximab)176 subcutaneous space; allows for increased dispersion and absorption of co-administered therapies enabling large volume (>5 ml)

Large volume Pushtronix System—The device adheres to Amgen’s Repatha® (evolocumab) single dose on-body the body, usually on the abdomen, and monthly dosing for cholesterol lowering177 infusors patients are hands-free during administration; 420 mg/3.5mL of Repatha® is delivered subcutaneously in nine minutes

enFuse is an on-body infusor drug delivery Enable Injections is in development device designed for patient self-administration partnerships with Genetech, Sanofi, and of high-volume drugs from 5 to 50 mL Apellis Pharmaceuticals for mAb delivery178

Slow release Medici Drug Delivery System: A matchstick- Intarcia and Numab collaboration focused on subdermal sized osmotic mini-pump designed to the development of once- or twice-yearly deliver a continuous flow of medication placed mono-specific and multi-specific antibodies under the skin for once- or twice-yearly dosing addressing diabetes, obesity and autoimmune indications179

Microneedles Transdermal alternative for drug delivery In preclinical development, testing using micron-scale needle structures bevacizumab and PD1 antibodies180–182

Electroporation Electroporation uses very short electrical Inovio’s Dengue/Zika mAb delivered with pulses to produce temporary pores of their CELLECTRA® 2000 device is in Phase I nanometer-range diameters in the intercellular clinical testing NCT03831503 lipid matrix of the skin, which allows for the delivery of large molecules

Jet injectors Jet injectors are a needle-free drug delivery Takeda Pharmaceutical and Portal Instruments device that delivers the biologic through a in development for Entyvio® (vedolizumab)183 pressurized liquid, clinically shown to be less painful and preferred by patients compared to a standard needle-based injection

policy makers can help guide the development of manufacturing standards with local regulatory products that are acceptable, affordable and feasible expectations can be complicated. to implement. Many MICs are capable of manufacturing small molecules and vaccines185, but manufacturing of Local production, local access biologics, including mAbs, mostly occurs in North America and Europe (Figure 15, next page)186. Another way to increase access to mAbs is to However, the number of mAb manufacturing facilities expand local or regional manufacturing capacity. is expanding in Asia and South America. India now has more USFDA-approved manufacturing facilities It’s estimated that around 79 per cent of all than any country except the US187 and their mAb pharmaceuticals in Africa are imported184. manufacturing capacity is growing. Importation can increase costs and lead to delays in access, or even drug shortages. But the economic Africa currently lacks the capacity to produce benefits of local manufacturing are dependent mAbs locally. Some stakeholders highlighted the on large volume demand128. And maintaining the need to train and develop personnel required for quality of the facility and mAb product and aligning the production and regulation of biologics before

37 | Expanding access to monoclonal antibody-based products availability + affordability = access

Figure 15: Concentration of global biopharmaceutical manufacturing

ussia 2.8% and astern urope urope and anada 36.6% 25.9% hina apan and 8.5% other Asia India 9.6% 8.1%

1.4% Africa Latin America Source: Baaj, A, 6.5% (2017) Tufts Center for the Study of Drug Development Report October

Examples of monoclonal antibody manufacturing facilities in Asia, Africa and South America

Manufacturer Country Method of production Status mAbxience Argentina Single-use bioreactor Operational188 PlantForm Brazil Plant transgenic Development unreported189 Butantan Brazil Continuous processing Under construction190 Libb Brazil Single-use bioreactor Operational191 WuXi Biologics China Single-use bioreactor Operational131 Pfizer China Single-use bioreactor Under construction131 Boehringer Ingelheim China Single-use bioreactor Under construction192 WuXi Biologics China Continuous processing Operational193 HJB China Continuous processing Operational194 Biocon India Hybrid model (undisclosed) Under construction195 Cipla India Continuous processing Operational196 Fujifilm Japan Continuous processing Operational197 Lonza Singapore Single-use bioreactor Operational198 WuXi Biologics Singapore Continuous processing Under construction199 iBio South Africa Plant transgenic Unreported200 Cipla South Africa Single-use bioreactor On hold201

investment in local manufacturing in Africa could be without the guarantee of a large market, local considered.* manufacturing is not feasible. “When it comes to antibodies, unless you have a big market it’s really One of the main challenges, according to not viable to set up [local manufacturing]. It’s only stakeholders, is that the market size for mAbs in when you produce very large volumes that you can many African countries is largely unknown, and drop your prices.”**

*Consultation with KEMRI-Wellcome Trust. 4 June 2019. Phone interview conducted by IAVI. Consultation with African Vaccine Manufacturing Initiative. 3 July 2010. Phone interview conducted by IAVI. Consultation with Clinton Health Access Initiative. 5 July 2019. Phone interview conducted by IAVI. Consultation with Kenyan Pharmacy and Poisons Board. 17th July 2019. In person interview conducted by IAVI. Consultation with Southern African Programme on Access to Medicines and Diagnostics. 17th July 2019. In person interview conducted by IAVI. **Professor Salim S. Abdool Karim, FRS Director: CAPRISA Professor of Global Health: Department of Epidemiology,

38 | Expanding access to monoclonal antibody-based products availability + affordability = access

Innovative approaches to intellectual property to expand access

One potential approach for facilitating greater negotiated together with a licence. MPP plans to access to mAbs and biosimilars in LMICs is the use release a special report on biologics soon. of voluntary licences. The Medicines Patent Pool (MPP), founded in 2010 by Unitaid, has successfully TRIPS agreements allow for compulsory licences utilised voluntary licences from pharmaceutical and exemptions to intellectual property protection companies to enhance access in LMICs to drugs for life-saving medicines in low-income countries. to treat HIV, TB and hepatitis C. Upon securing the But compulsory licensing has mostly been used voluntary licence from a pharmaceutical company for procurement of HIV/AIDS therapies in LMICs for a specific compound, the MPP sublicenses the and has not significantly improved access to other patent rights to manufacture and commercialise medicines in the least-developed countries203,204. the drug to one or more generic manufacturers to Compulsory licensing has not yet been utilised to support specified LMIC markets that have been broaden access to mAb products and there may be agreed upon with the pharmaceutical company. challenges to utilising this approach.

MPP undertook a feasibility study with the WHO to Some public-private partnerships are using assess whether they should expand their mandate to intellectual property rights to ensure that any include other infectious and non-infectious diseases products developed through their collaborations that impact LMICs, as well as biological products, will be promptly registered, manufactured in including mAbs202. They concluded that the MPP adequate quantities and distributed at reasonable mechanism could enhance access to biosimilars prices in developing countries. An increasing in LMICs, particularly for products with sizeable number of public and philanthropic funders, markets, such as for the treatment of breast cancer, including Wellcome, are requiring similar access provided that the technology transfer could be provisions for R&D they support205.

Implement new business models that prioritise access

Not all mAb products on the market today are priced Access-driven, innovative business models at thousands of dollars per dose. Biocon’s Canmab® are also necessary. By both implementing new — a biosimilar version of the breast cancer mAb technologies and developing sustainable lower- Herceptin®—sells for $100–$200 per dose in India, profit business models, mAbs could be made more significantly less than the $1,800 price per dose in affordable. Public-private partnerships such as the US. Innovative products Rabishield and Twinrab, the Utrecht Center for Affordable Biotherapeutics as illustrated on page 17, are priced at approximately (UCAB) and companies like the Serum Institute $20–$40 per dose. These examples provide proof of of India already aim to reduce mAb production concept that mAbs can be sold at dramatically lower costs, and prices, substantially. UCAB is targeting prices while still maintaining a viable, albeit lower- a price of $50 per dose for palivizumab, more than profit business model. 20-fold less than the average price of Synagis® in high-income countries, while some low-cost For mAbs to be globally accessible, prices may need manufacturers are targeting prices as low as to be even lower. How much lower will ultimately $5 per dose.* vary by country and disease area, but the goal is to ensure that affordability is not a barrier to access for Other models of collaboration between more of the world’s population. multinational pharmaceutical companies, governments, low-cost manufacturers and Efforts to lower mAb development and procurement agencies will also be required to manufacturing costs are essential to making mAbs ensure that both existing mAbs and those in more affordable. But alone, they are not sufficient. development are made more affordable.

*Stakeholder consultation with lost cost Indian manufacturer

39 | Expanding access to monoclonal antibody-based products availability + affordability = access

Alternate funding models to stimulate Initiative (IMI) supports many research consortia research and development for to jointly develop new antibiotics as well as infectious/neglected diseases alternatives such as mAbs212. The COMBACTE- NET (combating AMR in Europe) network213, For some infectious/neglected diseases and supported by IMI, is conducting a phase II trial drug-resistant bacterial infections, the burden is of MEDI3902, an investigational bispecific mAb overwhelmingly in developing countries and so there owned by Medimmune against Pseudomonas is not a strong market incentive for pharmaceutical aeruginosa. companies to invest in this research. As a result, alternate funding models are filling the gap. Today, • Venture capital initiatives, such as the Impact development of new therapies for infectious Repair Fund by Novo Ventures214 and the AMR and neglected diseases is mainly supported by Diagnostic Challenge215. public-sector and philanthropic sources206, which are creating alliances with governments, private • LifeArc, a leading UK medical research charity, companies and other public-sector entities to has partnered with Kymab, a clinical-stage support mAb research and development. biopharmaceutical company, to develop mAb- based therapeutics for a range of targets216. The public sector provided nearly two-thirds of the global infectious/neglected disease R&D funding • Some governments are also exploring a “Netflix”- in 2016, with contributions from the US, UK and like subscription-based model to incentivise R&D. European Commission topping the list. The US was The UK’s National Health Service will test the by far the largest funder, providing $1.5 billion in world’s first subscription-style payment model to funding in 2016, nearly three-quarters of the global encourage pharmaceutical companies to develop total207. new drugs for drug-resistant infections217. It works like this: Instead of paying companies based on Philanthropic entities including the Bill & Melinda the volume of medicine sold, the government Gates Foundation and Wellcome also provide will make upfront payments to pharmaceutical significant levels of R&D funding for infectious companies for access to their drugs based on their and neglected diseases. The Bill & Melinda Gates usefulness. Medical Research Institute, a non-profit biotech organisation, is focused on advancing products, including mAbs, to fight malaria, tuberculosis and Access-focused diarrheal diseases208. Wellcome, through their alternate business models Innovations Flagships, is committed to a broad portfolio approach to address neglected, tropical and A few of the alternative business models currently infectious diseases, and is exploring the affordability being used to develop more affordable mAbs are of mAbs and their potential role in enteric disease described below. treatment and prevention. Wellcome also has specific initiatives in epidemics, drug-resistant Utrecht Centre for Affordable Biotherapeutics infections and snakebite. (UCAB) The WHO and Utrecht University in The Netherlands Other funding sources include: initiated a technical collaboration in 2014 to create UCAB53. UCAB is pioneering access models to • CARB-X (Combating Antibiotic Resistant develop high quality and affordable biotherapeutics Bacteria)—a non-profit partnership financing through an association of distributed manufacturers the development of therapies, prevention and in MICs. diagnostics that target high-priority drug-resistant bacteria209. CARB-X is supported by multiple UCAB’s first pilot project, with technical oversight public and non-governmental organisation (NGO) and in-kind contributions from the WHO, is to sources and has supported two mAb projects so develop a low-cost biosimilar version of Synagis® far: funding Visterra Inc. to develop VIS705, a novel (palivizumab) against RSV with an anticipated broad-spectrum antibody-drug conjugate against estimated price of $250 per child for a full course multiple drug-resistant strains of Pseudomonas210, of fives doses53. UCAB has created a consortium, and funding Bravos Biosciences for the preclinical including a lead manufacturer (mAbxience) and local development of antibodies for multidrug resistant manufacturers (Libbs in Brazil, Medigen in Taiwan E. coli strains211. and Spimaco in Saudi Arabia) to support the project. UCAB anticipates filing the palivizumab biosimilar • The European Commission’s Innovative Medicines in 202353; however, determining market size is a key

40 | Expanding access to monoclonal antibody-based products availability + affordability = access

challenge,* especially if a new, single-dose mAb for biologics. Such models are anticipated to highlight RSV becomes available by then. the factors that directly influence affordability and availability at a local level. IAVI IAVI is working with partners to launch a set of MIT BioACCESS has so far focused on building initiatives to make mAb treatments and preventives the biomanufacturing component of their model. affordable and globally accessible. IAVI’s strategy is MIT’s Center for Biomedical Innovation has to enable wider access to mAbs through innovation developed two pre-competitive consortia related to and investments in product development and biomanufacturing. These initiatives bring academia, optimisation, low-cost manufacturing and novel industry and regulatory authorities together to business models. IAVI, in collaboration with Scripps better align incentives and work in ways that can Research, has been a leader in the discovery and advance the objective of providing sustained optimisation of potent HIV-specific bnAbs for access to more patients.** prevention and treatment. Much of IAVI’s work on HIV bnAbs has been supported by the US Agency for International Development218. Industry-led access models

IAVI is also partnering with the Serum Institute of Pharmaceutical companies are critical to planning India to produce affordable and accessible HIV for and supporting access to existing mAbs in bnAbs, as well as other mAb products219. With developing countries. An important component support from the UK Department for International of industry-led access initiatives in LMICs are Development, IAVI has formed a research patient-access schemes. These schemes between consortium on snakebite to identify and engineer payers (including ministries of health, private antibodies to treat envenoming, a disease caused insurance companies and procurement agencies) by snake venom220. IAVI and its partners are also and pharmaceutical companies started out in applying their experience in HIV to the discovery high-income countries, but are now increasingly and development of mAbs to prevent and treat being used in middle-income countries in Latin a variety of emerging and established infectious America, Asia and Africa to enable patient access diseases including drug-resistant bacteria and to innovative medicines. COVID-19221. One type of patient access scheme that is more MIT BioACCESS common in developing countries is company- The development of new health technologies for led, patient-assistance programmes. These NCDs is predominantly led by pharmaceutical programmes seek to increase access to innovative companies. Although NCDs are now the most medicines and address a lack of healthcare common cause of death and disability worldwide, infrastructure. accounting for 70 per cent of global mortality, there has not been a significant expansion of resources or Both Roche and Takeda have launched patient- attention from international donors or governments assistance programmes to provide mAb therapies to address this escalating disease burden in to patients who couldn’t otherwise afford them. developing countries222. In 2017, development Roche is partnering with the governments of China, assistance for health from major funding sources Pakistan and the Philippines to supply their breast (bilateral assistance, philanthropies, NGOs, etc.) cancer mAb Herceptin®113. In Pakistan Roche splits totaled over $37 billion, while funding for NCDs was 50 per cent of the cost of Herceptin® treatment with less than $1 billion)206. the federal government for patients in need.

MIT BioACCESS, part of the MIT’s Center for In China, the company collaborates with the Cancer Biomedical Innovation, is addressing the complex Foundation (CFC) and the Ministry of Health to issues surrounding global access to biologics, donate eight cycles of Herceptin® after the patient in particular for NCDs in resource-constrained has completed the first six cycles. Before this settings. Through an “Access-by-Design” programme fewer than 15 per cent of women in the framework, this group is utilising a systems-based public health system in China received Herceptin®. approach to model the impact different innovations Now, more than twice that amount complete the full could have on manufacturing and delivery of NCD course of treatment. To date, over 60,000 women

*Consultation with Utrecht Centre for Affordable Biotherapeutics. 9 August 2019. Phone interview conducted by IAVI. **Consultation with MITBioAccess team. 15 and 29 August 2019. Phone and email interviews conducted by IAVI.

41 | Expanding access to monoclonal antibody-based products availability + affordability = access

have accessed Herceptin® through this programme, standard discounts or tiered pricing. The patient- which has also made Chinese physicians more specific approach takes into consideration what willing to prescribe the mAb223. is an affordable price for each individual, rather than determining it more broadly on a country or Takeda’s access strategy focuses on providing some even community level. This patient assistance of the company’s most innovative medicines as well programme is a useful case study for access to as strengthening local R&D and healthcare capacity novel mAb therapies, and if scaled up and applied in LMICs. The company offers patient-assistance to other mAbs, could have a significant impact on programmes in 14 countries in Asia, Africa, Latin global access. America, the Middle East and Europe. As a result of these programmes, Takeda has provided more Takeda’s Access to Medicines (AtM) R&D initiatives than 125,000 patients with treatment, screened also aim to share knowledge and build skills to over a million patients for cancer, hypertension strengthen local R&D and healthcare capacity and diabetes, and trained over 4,000 healthcare in LMICs. This includes supplying medical and providers and community health workers to improve scientific equipment and developing research patient care224. capabilities224.

Nearly 700 patients have been treated with Takeda’s Other multinational companies are also starting most innovative antibody-based medicines — to recognise the need for access strategies to Adcetris®, an antibody-drug-conjugate for relapsed provide innovative medicines, including mAbs, in and refractory Hodgkins lymphoma, and Entyvio®, LMICs. The Access to Medicines Foundation’s a mAb product to treat inflammatory bowel (AMF) recent ten-year analysis noted that disease224—as a result of these patient-assistance companies are gradually changing their business programmes. models and are setting access targets for products outside of high-income countries225. However, The affordability of Adectris® and Entyvio® were only a few companies so far are supporting assessed by an independent third party, Axios, which comprehensive access agendas (covering R&D, created an individualised payment scheme for each pricing, manufacturing, distribution, licensing, patient to ensure they could complete their entire capacity building and product donations), and only course of treatment even if they could not pay for a limited number of diseases and countries are it in full. This personalised pricing is distinct from covered.

Establish procurement and delivery models to enable greater acess

Access to existing health technologies for infectious are not yet included in any of these existing diseases in low-income countries and some middle- donor-funded procurement agencies. income countries is largely facilitated by government and philanthropic funding pooled through UN- Gavi, the Vaccine Alliance, which was backed agencies like Gavi (vaccines), The Global established in 2000, gathers large-scale donor Fund (HIV, TB and malaria) and UNICEF (children’s funding (approximately $9.1 billion from 2016- wellbeing), or the US government-supported 2020)227 and uses it to fund the purchase and PEPFAR programme (HIV). Pooled procurement is procurement of vaccines for the poorest nations akin to buying in bulk—these agencies combine in the world. Gavi considered providing mAb- several buyers (typically governments of various based post-exposure prophylaxis (PEP) for countries) into a single entity and purchase vaccines rabies but instead decided to support rabies or medicines on behalf of those buyers at discounted vaccines for PEP beginning in 2021228. Gavi also prices. Pooled procurement has helped make considered supporting mAbs for prevention of vaccines and medicines available and affordable in RSV, but initially supported RSV vaccines and the poorest countries in the world226. However, mAbs not mAbs.

42 | Expanding access to monoclonal antibody-based products availability + affordability = access

Still, a Gavi-like financing model, which has been highly successful for childhood vaccines, could be a viable solution for broadening access to mAbs.* Gavi and The Global Fund are both considering including mAbs in their long-term planning,** and it is anticipated that UN-backed procurement agencies, specifically those involved in vaccines, may eventually support procurement of mAbs.*** However, as UN-backed procurement agencies depend upon prequalification by the WHO, their ability to support procurement of mAbs will be limited unless more mAb products undergo the prequalification process.

Other agencies involved in drug procurement, including The Global Fund, are open to considering including mAbs for infectious/neglected diseases in their long-term planning.**** Other procurement models will likely also be required to widen access to mAbs for non-communicable diseases.

*Consultation with Churches Health Association of Zambia. 4 July 2019. Phone interview conducted by IAVI **Consultation with GAVI, 4 July 2019. Consultation with The Global Fund .17 June 2019. Phone interviews conducted by IAVI ***Consultation with UNICEF 13 September 2019. Phone interview conducted by IAVI. Consultation with The Global Fund 17 June 2019. Phone interview conducted by IAVI ****Consultation with GAVI, 4 July 2019. Consultation with the Global Fund.17 June 2019. Phone interviews conducted by IAVI

43 | Expanding access to monoclonal antibody-based products A roadmap for expanding global access to monoclonal antibodies

Monoclonal antibody-based therapies are unavailable and unaffordable for millions of people around the world. The goal of this report is to catalyze new ways of thinking, greater collaboration and new ways of doing business to address this inequity.

The following roadmap details specific actions to expand access to existing monoclonal antibodies for both non-communicable and infectious diseases and to pave the way for expeditious development and introduction of future monoclonal antibody products. If the desired outcomes are reached, there will be substantial progress towards advancing global access.

44 | Expanding access to monoclonal antibody-based products GOAL Increase the availability of mAbs 1 in low- and middle-income countries

PART I: ADVOCACY Monoclonal antibodies save lives: Spread the word

Action Increase awareness among governments, ministries of health and patients that mAbs have substantial OUTCOMES clinical and public health value Advocacy networks Who’s Government agencies, global health organisations, academic and public research needed institutions, funders, non-profit product developers and bio-pharmaceutical industry, established that focus on non-governmental organisations (NGOs) and civil society groups increasing the availability of mAbs in low- and Bolster advocacy efforts related to mAb access middle-income countries in low- and middle-income countries

Government agencies, global health organisations, academic and public research institutions, funders, non-profit product developers and bio-pharmaceutical industry, Key barriers addressed non-governmental organisations (NGOs) and civil society groups that prohibit broader availability of mAbs in public health systems Dispel myths that mAbs can’t be affordable and that production costs can’t be lower by communicating the findings of this report Value proposition Global health organisations, academic and public research institutions, established, using manufacturers, non-profit product developers and bio-pharmaceutical industry health and economic modeling studies, for the Assess the barriers to making mAbs available in public introduction of mAbs in health systems in low- and middle-income countries low- and middle- income countries Government agencies, health care providers, global health organisations, academic and public research institutions, health technology assessment groups, non-governmental organisations (NGOs) and civil society groups Goals related to mAb development and Conduct studies to model the health and economic access included in impact of introducing mAbs in developing countries existing global health Government agencies, global health organisations, academic and public research agendas (examples institutions, health technology assessment groups include: UN-backed Sustainable Development Promote access through global health agendas Goals, Universal Health Coverage, Wellcome Influencers and leaders of global health organisations, including the Bill & Melinda Gates Foundation, Wellcome, Unitaid; policy makers and influencers Flagship Initiatives associated with universal healthcare, non-governmental organisations (NGOs) and the Coalition for and civil society groups Epidemic Preparedness Innovations) Include mAbs in epidemic/pandemic preparedness initiatives as an important complement to vaccines

Government agencies and ministries of health, global health organisations, Commitments secured on non-governmental organisations (NGOs) and civil society groups calls to action for global access to mAbs at a Key Opinion Leader meeting Convene key opinion leaders from private, public and held by Wellcome and philanthropic entities to align on access pathways IAVI Wellcome, IAVI, all stakeholders mentioned above

45 | Expanding access to monoclonal antibody-based products PART II: POLICY AND REGULATORY Support broader registration and availability of monoclonal antibodies across the globe

Action Develop disease-specific guidelines for mAbs to ensure products are designed with local population OUTCOMES needs in mind

Who’s Non-profit product developers, bio-pharmaceutical industry, manufacturers; More mAbs are registered needed global health organisations (including WHO); governments; national regulatory agencies; stringent regulatory authorities in more low- and middle- income countries faster and included in public Harmonise and expand existing policy and regulatory health programmes pathways in low- and middle-income countries

Non-profit product developers, bio-pharmaceutical industry, manufacturers; global health organisations (including WHO); government agencies; national regulatory More mAb products agencies; stringent regulatory authorities; African Medicines Agency; African Vaccine Regulatory Forum are developed based on individual, local and regional preferences Encourage product developers to engage with the WHO early in the development process to clarify pathways for inclusion in policy guidelines and to Initiatives including enable prequalification. the African Medicines

WHO, non-profit product developers and bio-pharmaceutical industry Agency and the African Vaccine Regulatory Forum help address Identify barriers to adding mAbs to the WHO’s Model regulatory barriers to List of Essential Medicines or in getting more mAbs mAb licensure in Africa prequalified by the WHO

WHO, global health organisations, government agencies, non-profit product developers and bio-pharmaceutical industry More mAbs are prequalified by the WHO, added to WHO’s Identify barriers to mAbs being added to national essential medicines lists following their approval EML and added to by stringent regulatory authorities, their being essential medicines list prequalified or added to the EML in developing countries

Government agencies, ministries of health, WHO, national regulatory agencies, health technology assessment groups Access is expanded to mAbs that are either Expand use of collaborative regulatory initiatives prequalified or included between stringent and national regulatory authorities in essential medicines list to address limited regulatory capacity in developing countries

WHO, non-profit product developers and bio-pharmaceutical industry, African Medicines Agency, African Vaccine Regulatory Forum, national regulatory authorities

46 | Expanding access to monoclonal antibody-based products GOAL Make mAbs more affordable 2 in low- and middle-income countries

PART I: INNOVATION Invest in and deploy innovative technologies to lower monoclonal antibody development costs

Action Engage public-private partnerships and funders to drive mAb innovation with an end-to-end perspective OUTCOMES

Who’s Funders, non-profit product developers and bio-pharmaceutical industry, global needed health organisations, academic and public research institutions Increased and diversified funding available Develop and refine target product profiles that for the research and prioritise affordability and acceptability for low- development of mAbs for and middle-income countries at all stages of mAb global health discovery and development.

Non-profit product developers and bio-pharmaceutical industry, global health Proven technologies and organisations, academic and public research institutions, technology companies platforms are applied to discovery, optimisation Ensure that appropriate technologies (and and development of companion diagnostics if needed) are integrated pipeline mAbs that early into product development and are responsive can prevent and treat to the specific diseases, patient populations and infectious and neglected communities in which they will be introduced diseases, including drug-resistant bacterial Non-profit product developers and bio-pharmaceutical industry, technology companies, global health organisations, academic and public research infections, epidemics institutions, funders such as Ebola and pandemics such as Develop and apply new technologies and platforms COVID-19 that have the potential to lower costs throughout the production process from antibody isolation to manufacturing to delivery Proven technologies and platforms are Funders, non-profit product developers and bio-pharmaceutical industry, applied to dramatically manufacturers, academic and public research institutions, technology companies, global health organisations lower production and delivery costs of licensed innovative and biosimilar Apply technological lessons learned from developing mAb products and producing lower-priced biosimilars and some lower-priced innovative mAbs to further lower prices of marketed mAbs as well as those in development

Low-cost LMIC manufacturers, biosimilar companies

47 | Expanding access to monoclonal antibody-based products PART II: BUSINESS MODELS Create new business models that enable different market approaches in low-, middle- and high-income countries

Action Establish collaborations between public, private and philanthropic entities to expand access OUTCOMES to innovative and biosimilar mAbs in low- and middle-income countries Public-private Who’s Non-profit product developers, bio-pharmaceutical industry, needed manufacturers; funders; global health organisations; academic and public partnerships focused research institutions on developing mAbs for infectious/neglected Expand existing but limited industry-led patient diseases establish access plans that focus on enhancing access to comprehensive and innovative medicines as well as strengthening innovative plans for health systems, diagnostic capabilities and research global commercialisation capacity in developing countries of and access to eventual Non-profit product developers, bio-pharmaceutical industry, manufacturers; products governments global health organisations; funders

More companies Develop or expand global pricing frameworks establish scalable for mAbs, including the use of second brands, to introduce existing biosimilar and innovative mAbs patient access schemes in low- and middle-income countries to expand access to existing mAbs Non-profit product developers, bio-pharmaceutical industry, manufacturers; health technology assessment groups; government agencies More affordable Identify donor-funded procurement agencies products, including that can support broader access to mAbs second brands and in developing countries biosimilars, are introduced in low- and Global health organisations, funders middle-income countries

Explore alternate manufacturing and supply chains in different regions that enable market differentiation A Gavi-like model and provision of more affordable mAbs in of procurement is low- and middle-income countries established for mAbs to enable a lower cost and Non-profit product developers, bio-pharmaceutical industry, manufacturers; procurement groups; government agencies sustainable supply of antibodies in developing countries Identify creative solutions to manage intellectual property rights related to mAbs that encourage innovation, while also prioritising access to affordable Alternate intellectual mAb products property agreements

Unitaid; Medicines Patent Pool; non-profit product developers, bio- that prioritise access pharmaceutical industry, manufacturers; global health organisations are implemented in developing countries

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The IAVI-Wellcome project team IAVI: Ayesha Sitlani (principal investigator), Lisa Gieber (information specialist), Kristen Abboud (consultant, scientific writing), Hester Kuipers (advocacy), Maggie Keane (access), Shelly Malhotra (access), Rajat Goyal (India team), Pritha Aggarwal (India team), Vincent Muturi-Kioi (Africa team), Yolanda Moyo (Africa team), Karie Youngdahl (communications), Nicole Sender (communications), Jackson Dykman (consultant, graphic design) Wellcome: Lindsay Keir (Innovation partner, project lead), Sari Watson (Innovations operations, head)

Acknowledgements We would like to thank experts (list of stakeholders, Appendix) who shared valuable insights and information that helped shape our analyses and call to action. We also thank them for their thoughtful review of sections of the document. A special thanks to the IAVI leadership including Mark Feinberg (CEO) and Ana Céspedes (COO), the IAVI Scientific Advisory Board, and Wellcome’s Affordable Innovation for Global Health Flagship team and Scientific Advisory Board who provided valuable insights, sponsorship and careful review of the document.

This report has been commissioned by Wellcome. Copyright © IAVI and Wellcome. It is distributed under the terms of the Creative Commons CC-BY licence, which permits unrestricted use and redistribution of the data or text provided that the original author and source are credited. If you do edit the text, then you must acknowledge this on the republished article. We suggest that you cite this report as follows: IAVI/Wellcome (2020). “Expanding access to monoclonal antibody-based products: A global call to action.”

This work was supported by Wellcome Innovations funding through the Affordable Innovations for Global Health flagship grant [215847].

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